AU2240299A - 2,3,4,5-tetrahydro-1h-(1,4)-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors - Google Patents

2,3,4,5-tetrahydro-1h-(1,4)-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors

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Publication number
AU2240299A
AU2240299A AU22402/99A AU2240299A AU2240299A AU 2240299 A AU2240299 A AU 2240299A AU 22402/99 A AU22402/99 A AU 22402/99A AU 2240299 A AU2240299 A AU 2240299A AU 2240299 A AU2240299 A AU 2240299A
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Australia
Prior art keywords
alkyl
tetrahydro
benzodiazepine
methoxybenzenesulfonyl
ch
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Abandoned
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AU22402/99A
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Jay Donald Albright
Efren Guillermo Delos Santos
Xuemei Du
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Wyeth Holdings LLC
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Wyeth Holdings LLC
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Priority to US1437498A priority Critical
Priority to US09014374 priority
Application filed by Wyeth Holdings LLC filed Critical Wyeth Holdings LLC
Priority to PCT/US1999/001325 priority patent/WO1999037625A1/en
Publication of AU2240299A publication Critical patent/AU2240299A/en
Application status is Abandoned legal-status Critical

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D243/00Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1,4
    • C07D243/10Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1,4 condensed with carbocyclic rings or ring systems
    • C07D243/141,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Description

WO 99/37625 PCT/US99/01325 -1 2,3,4,5-TETRAHYDRO-1H-[1,4]-BENZODIAZEPINE-3-HYDROXAMIC ACIDS AS MATRIX METALLOPROTEINASE INHIBITORS 5 FIELD OF INVENTION This invention relates to 4-(4-substituted-benzenesulfonyl)-2,3,4,5-tetrahydro 1H-[l1,4]benzodiazepine-3-hydroxyamic acids which act as matrix metalloproteinase 10 inhibitors. The compounds of the present invention are useful in disease conditions mediated by matrix metalloproteinases, such as tumor growth, osteoarthritis, rheumatoid arthritis and degenerative cartilage loss. BACKGROUND OF THE INVENTION 15 Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc-containing endopeptidases consist of several subsets of enzymes, including collagenases, stromelysins and gelatinases. Of these, the gelatinases have been shown to be the MMPs most intimately involved with the growth 20 and spread of tumors. For example, it is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also 25 recently been shown to have a gelatinase component to its pathology as reported in "Matrix Metalloproteinases, Novel Targets for Directed Cancer Therapy", Drugs and Aging, 11:229-244 (1997). Other conditions mediated by MMPs include restenosis, MMP-mediated 30 osteopenias, inflammatory diseases of the central nervous system, skin aging, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal 35 membranes, inflammatory bowel disease, periodontal disease, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of WO 99/37625 PCT/US99/01325 -2 prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia. ocular tumors, ocular angiogenesis/ neo-vascularization and corneal graft rejection. Studies relating to these conditions are set forth, e.g., in "Recent Advances in Matrix Metalloproteinase Inhibitor Research", R. P. Beckett et al., Research Focus, 1:16-26, 5 (1996); Curr. Opin. Ther. Patents, 4(1): 7-16, (1994); Curr. Medicinal Chem., 2: 743 762, (1995); Exp. Opin. Ther. Patents, 5(2): 1087-110, (1995); Exp. Opin. Ther. Patents, 5(12): 1287-1196, (1995); "Inhibition of Matrix Metallo-proteinases: Structure Based Design", Current Pharmaceutical Design, 2:524-661, (1996). "Matrix Metalloproteinase Inhibitor Drugs", Emerging Drugs, 2:205-230 (1997). 10 TNF-o converting enzyme (TACE) catalyzes the formation of TNF-oa from membrane bound TNF-a precursor protein. TNF-a is a pro-inflammatory cytokine that is believed to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central 15 nervous system, inflammatory bowel disease, insulin resistance and HIV infection, in addition to its well-documented antitumor properties. Research with anti-TNF-a antibodies in transgenic animals has demonstrated that blocking the formation of TNF-a inhibits the progression of arthritis. This observation has recently been extended to humans as described in "TNF-ax in Human Diseases", Current 20 Pharmaceutical Design, 2:662-667 (1996). It is expected that small molecule inhibitors of MMPs and TACE would have the potential for treating a variety of disease states. Although a variety of MMP and TACE inhibitors are known, many of these molecules are peptidic and peptide-like which 25 demonstrate bioavailability and pharmacokinetic problems. Long acting, orally bioavailable non-peptide inhibitors of MMPs and/or TACE would thus be highly desirable for the treatment of the disease states discussed above. U.S. Patent No, 5,455,258 discloses 2-substituted-2-(arylsulfonylamino) 30 hydroxyamic acids and their use as MMP inhibitors. WO 97/18194, discloses N (arylsulfonyl)tetrahydroisoquinolone-hydroxyamic acids and related bicyclic derivatives thereof and their use as MMP inhibitors. WO 97/20824 discloses 1-(arylsulfonyl)-4 (substituted)piperazine-2-hydroxyamic acids, 4-(arylsulfonyl) morpholine-3 hydroxyamic acids, 4-(arylsulfonyl)-tetrahydro-2H,1,4-thiazine-3-hydroxyamic acids, 35 3-(substituted-l1-(arylsulfonyl)hexahydro-2-hydroxyamic acids and related compounds as useful MMP inhibitors.

WO 99/37625 PCT/US99/01325 -3 SUMMARY OF THE INVENTION This invention relates to novel derivatives of substituted 2.3,4,5-tetrahydro-1 H [1,4]benzodiazepine-3-carboxylic acid hydroxyamide which exhibit inhibitory activity against MMPs. The compounds of the present invention are represented by the 5 following formula 1 0 11 SO 2 \& R 4 HOHN N R, R R2 N I R3 1 wherein 10 R is selected from hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F,

NH

2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 ,

-SO

2

NH

2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen;

R

4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, - R, ,-R , 0 S / kR, R, R, N N -0-- N N - R ,- SR , or 15 -- R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ;

R

1 and R 2 are each, independently, hydrogen or CH 3 ;

R

3 is (C 1 - C 8 )alkyl, NH 2

CH

2 CO-, (Cl - C 6 )alkylNHCH 2 CO-, HO(CH 2 )mCO-, HCO-, Aryl(CH 2 )nCO-, Heteroaryl(CH 2 )nCO-, (C1 - C 3 )alkyl-O-(CH 2 )nCO-,

(C

1 - C 3 )alkylCO-, (C 1 - C 3 )alkylCO-NHCH 2 CO-, (C 3 - C7)cycloalkylCO-, WO 99/37625 PCTIUS99/01325 -4

(C

1 - C 3 )alkvISO 1 )-. AryI(CH 2 )nSO 2 -- Heteroary](CH-) SO 2 - (C 1 - C 3 )alkvl-O

(CH

2 )mSOI 2 . (Cl - C 3 )alkyl-O-(CH 2 )m, (C 1 - C 3 )alkvl-O-(C 1 - C 3 )zlkVl-O-(C 1

C

3 )alkyl. HO-(C I - C 3 )alkyl-O-(C I - C 3 )alkyl. Aryi-O-CH- 2 CO-. Heteroarvl-O-CH- 2 CO-, AryICH=CHCO-. HeteroarvlCH=CHCO-.

(C

1 - C 3 )alkvlCH=CHCO-, 0 0 CHC- Qr -CH ,OC-NHCH-,C0 AryI(C 1 - C 3 )alkyl, Heteroaryl(C 1 I C 3 )alkyl, AryICH=CHCH 2 -, HeteroarylCH=CHCH 2 -, (C 1 I C 6 )alky]CH=CHCH 2 -. co- \ c o- co m N 10 0 nw C-n M -CC- f t-Co R'OCH-, CH(OR')CO-, (R'OCH 2

)

2 C(R')CO-,

CH

3 -r,,(C 1 - C 3 )aikylCH=CH-CO- Q ( 6ak]O \-)l-I C 6 )aikyICO- (C 1 I C 3 )alkyICONHCO-,

L,,N(CIC

6 )akylC0 QN(CI C 6 )alkyICO- N-(IC)lyC--C-6akl CH (l- C 6 )alkylCO- t-Boc-N N-(C 1 - C 6 )alky]CO-' 0- 0 11 /--\ X :Tc I Et0Cr"yN(C1 - C 6 )alkylCO 15 WO 99/37625 PCT/US99/01325 -5 N- (C1 - C 6 )alkylCO - CH 3 R' O CO

[(C

l - C 6 )alkyl] 2

-N-(C

1 - C 6 )alkyl CO-. or (C 1 - C 6 )alkyl-NH-(C 1 - C 6 )alkylCO-: wherein 5 m= 1 to3: n = O to3; Aryl is x S and R Heteroaryl is xx ;5- X Xn N S 0 Xo xx - -N N O S Nt~r O .. NN ,or I I 10 R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 and R and R' are as defined above; L is hydrogen, (C 1

-C

3 )alkyl, -CN, -OR', -SR', -CF 3 ,

-OCF

3 , Cl, F, NH 2 , -NH-(C 1 C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2

NH

2 , 15 -SO 2 N(R')(R'), -N(R')COCH 2 0-(CI - C 3 )alkyl, CONH- Y CONH- Y -

CONH

CONH- or Y\ S 0 WO 99/37625 PCT/US99/01325 -6 M is N Y YY/ NS 0 N 'N N N ,' N \~N R I R , -N Ny R'-N N- , OCO-N N, N tBoc -N N- N- N .N- , or N(R')(R') where R' is as defined above; 5 W is O, S, NH or N(C 1 - C 3 )alkyl; Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C 1 - C 3 )alkyl, O

(C

1 - C 3 )alkyl, or -CH 2 OH; and pharmaceutically acceptable salts thereof. 10 When used herein the term C1-C3 alkyl covers methyl, ethyl, n-propyl and i-propyl groups. When used herein the term C 1-C6 alkyl covers, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl and pentyl groups. When used herein the term C3-C7 cycloalkyl covers saturated and unsaturated cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 15 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl and 2-cyclobutenyl. R is suitably hydrogen, halogen or (C1-C3)alkyl, for example hydrogen, chloro or methyl. R1 is suitably hydrogen. R2 is suitably hydrogen. R4 is suitably (C 1-C6 alkyl)-O-, for example methoxy. R3 is suitably selected from the group: (C 1-C3)alkyl SO2-, aryl(CH2)nSO2-, (C1-C3)alkyl-CO-, aryl(CH2)nCO-, heteroaryl(CH2)nCO-, WO 99/37625 PCT/US99/01325 -7 (C l-C3)alkyl-O-(CH2)nCO-, (C3-C7)cycloalkyl-CO-, (C 1-C3)alkyl-O-(CH2)m- or aryl(C 1-C3)alkyl-, for example methylsulphonyl, n-propylsulphonyl, 4-methyl phenylsulphonyl, 4-methoxyphenylsulponyl, methylcarbonyl, 3 trifluormethylcarbonyl, 2-phenylethylcarbonyl, methoxymethylcarbonyl, 5 cyclopropylcarbonyl, cyclohexylcarbonyl, 2-methoxyethyl, phenylcarbonyl, 2-methyl 5-fluorophenylcarbonyl, 4-biphenylcarbonyl, 2-biphenylcarbonyl, 2,4 dichlorophenylcarbonyl, phenoxymethylcarbonyl, phenylcarbonyl, 4 trifluoromethylphenylcarbonyl, 2-imidazol- I -yl-phenylcarbonyl, 2-morpholin-4-yl phenylcarbonyl, 4-ethoxyphenylcarbonyl, 4-(4-methyl-imidazol-1-yl)-2-choloro 10 phenylcarbonyl, 2,4-dimethoxyphenylcarbonyl, 4-methyl-piperazin- 1 ylmethylcarbonyl, 3-pyridinylcarbonyl, 2-thienylcarbonyl, 4-pyridinylcarbonyl, 2 furanylcarbonyl or benzyl. Preferably, the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , 15 -OCF 3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 ,

-CONH

2 , -SO 2

NH

2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen;

R

4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, - I RI , s- RI 0 1S F/kRI R, R, - NN , - -S - R , - S-R , or 20 R wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ;

R

1 and R 2 are each, independently, hydrogen or CH 3 ;

R

3 is (C 1 - Cg)alkyl, NH 2

CH

2 CO-, (C 1 - C 6 )alkylNHCH 2

CO-

,

HO(CH

2 )mCO-, HCO-, Aryl(CH 2 )nCO-, Heteroaryl(CH 2 )nCO-, (C 1 - C 3 )alkyl-O-(CH 2 )nCO-,

(C

1 - C 3 )alkylCO-, (C 1 - C 3 )alkylCO-NHCH 2 CO-, (C 3 - C 7 )cycloalkylCO-, 25 Aryl-O-CH 2 CO-, HeteroarylOCH 2 CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-,

(C

1 - C 3 )alkylCH=CHCO-, WO 99/37625 PCT/US99/01325 -8 ©0_1o0-_

CH

2 OC- CH 2

OC-NHCH

2

CO

wherein m= Ito 3; n=0to3; Aryl is X and 5 R' Heteroaryl is x x .,x X> N 0 S I R' N , N , or X O N N R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 wherein R and R' are as 10 defined above; and pharmaceutically acceptable salts thereof. More preferably, the compounds of the present invention are those of formula 1 wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 ,

NH(C

1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2

NH

2 , 15 -SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen;

R

4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, WO 99/37625 PCT/US99/01325 -9 - R ,_s RI /'RI R / I RI R, R , or R wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ;

R

1 and R 2 are each, independently, hydrogen or CH 3 ;

R

3 is

CH

3 -N N(C 1 - C 3 )alkylCH=CH-CO- , N-(CI - C 6 )alkylCO N-(Cl - C 6 )alkylCO- , (CI - C 3 )alkylCONHCO-, N-(C-C0)alkylCO Q N-(C I - C 6 )alkylCO- , N-(C-C 6 )alkylCO- , N-(CI-C 6 )alkylCO / 1- / -- \

CH

3 - JN(C - C 6 )alkylCO- , t-Boc-N N-(C 1 - C 6 )alkylCO-, CO- 0 EtOC ~.N(C I - C 6 )alkylCO 5 R' 0' N-(Cl - C 6 )alkylCO C3 R "- \ R' O CO

[(C

1 - C 6 )alkyl] 2

-N-(C

1 - C 6 )alkyl CO-, or (C 1 - C 6 )alkyl-NH-(C 1 - C 6 )alkylCO-, wherein R' is as defined above; and pharmaceutically acceptable salts thereof. 10 WO 99/37625 PCT/US99/01325 - 10 It is more preferred that the compounds of the present invention include those of formula 1 wherein R is hydrogen, (C l - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2,

-SO

2

NH

2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) 5 alkyl or hydrogen;

R

4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-,

-

I , - R RI R p R, - N N , - - S N N R/ , S R ,or R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; RI and R 2 are each, independently hydrogen or CH 3 ;

R

3 is (C 1 - C 3 )alkylSO 2 -, Aryl(CH 2 )nSO 2 -, Heteroaryl(CH 2 )nSO 2 -, or (C 1 - C 3 )alkyl 10 O-(CH 2 )m-SO 2 , wherein m= I to3; n = 0to 3; Aryl is x and

R'

WO 99/37625 PCT/US99/01325 -11 Heteroaryl is - , X . X X N ? 0) N 0 S \X otr \ r- N ,--N I R' N , NX ,or X O N N II R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof. 5 A further, more preferred embodiment of the present invention includes compounds represented by formula 1 wherein R is selected from hydrogen, (Cl - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 ,

-OCF

3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , 10 -CONH 2 , -SO 2

NH

2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen;

R

4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, I- RI, -0 I RI R-_X RR 1 ' R - 1 1 - O- N N , - - S N N - R , - S R , or -- R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ;

R

1 and R 2 are each, independently hydrogen or CH 3 ; 15 R 3 is (C 1 - C 8 )alkyl, Aryl(C 1 - C 3 )alkyl, Heteroaryl(C 1 - C 3 )alkyl, ArylCH=CHCH 2 , HeteroarylCH=CHCH 2 -, or (C 1 - C 6 )alkylCH=CHCH 2 -, wherein WO 99/37625 PCT/US99/01325 - 12 Aryl is X Iand R' Heteroaryl is ' x .,x >, x N-X X X 0 N 0 S) IN , < N ,or X O N N I I R' R' 5 wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 and R and R' are as defined above; and pharmaceutically acceptable salts thereof. Additionally preferred compounds of the present invention include those of formula 1 wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, 10 F, NH 2,

NH(C

1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , SO 2

NH

2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen;

R

4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, -oK2R ,, _ O R-,

-

R1 , , R R , , - N 1N , - O -- S J N N -OR , -SR , or -R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; 15 R 1 and R 2 are each, independently hydrogen or CH 3

;

WO 99/37625 PCT/US99/01325 - 13

R

3 is Y YM CO- CO-

CO

M N 0 co- co MM Y- O-~CO-CO C -CO, or

YCO

wherein m= 1 to3; n=0to3; 5 L is hydrogen, (C 1 - C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , -NH-(CI - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2

NH

2 ,

-SO

2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, CON Y CONH- Y r CONH , NH-,or 4S 0 10 M is Y0Y y ' N S I R' N Y R' I R'-N N- , -OCO-N N , N- WO 99/37625 PCT/US99/01325 -14 tBoc -N N- 0 N- N /N- , or N(R')(R') where R' is as defined above; W is O, S, NH or N(C 1 - C 3 )alkyl; Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C 1 - C 3 )alkyl, O 5 (C 1 - C 3 )alkyl, or -CH 2 OH, and pharmaceutically acceptable salts thereof. The compounds of the invention may be prepared by reacting an appropriate acid halide such as the acid chloride or bromide with hydroxylamine. The acid halide may be prepared by reacting the corresponding acid or a metal salt thereof with an 10 activating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride, thionyl bromide, (chloromethylene)dimethylammoniumchloride or (bromomethylene)dimethyl ammonium bromide. The subsequent reaction of the acid halide with hydroxylamine may suitably be performed in situ. 15 Metal salts may be prepared by reacting a ester of formula Ia o II SO2 R4 C N R/ N 2 1 R R

R

2 N R3 la wherein R 2 1 is (Ci- 6 )alkyl, benzyl or arylalkyl and all other groups are as defined above, with a base such as lithium hydroxide, potassium hydroxide, sodium hydroxide or barium hydroxide. This may suitably be performed in a solvent such as a (C 1

-C

8 ) 20 alcohol, tetrahydrofuran, N,N-dimethylformide or p-dioxane in the presence or absence of water. The resulting metal salt may be directly converted to the desired product or it may first be converted to the acid, e.g. by treating it with aqueous hydrochloric acid or acetic acid. Alternatively the ester of formula la may be converted to its acid by treatment with an aqueous mineral acid such as hydrochloric acid, hydrobromic acid or 25 trifluoroacetic acid and the acid converted to the desired product as described above. The compounds of formula 1 may be advantageously prepared according to Reaction Schemes I to 7. Variations in these schemes may be made to improve productivity without negatively impacting the amount and nature of the product, by WO 99/37625 PCT/US99/01325 - 15 means that will be recognized by those skilled in the art. For example, reactive groups may be blocked with suitable blocking moieties which may then be deblocked under standard conditions (for instance, hydroxy groups may be protected with trimethylsilyl or t-butyl-dimethylsilyl moieties which are then removed in a later reaction step). 5 In general, the compounds of Fonrmnula 1 are synthesized from an alkyl ester (such as methyl, ethyl, t-butyl and the like) of serine, threonine, or 3,3-dimethyl-3 hydroxypropionic acids. One reaction pathway is shown in Reaction Scheme 1. It is noted that methyl esters are shown in all of the Reaction Schemes, however, it is to be understood that the use of methyl esters is for purposes of illustration only, and other 10 suitable alkyl esters or benzyl esters may similarly be used. In Reaction Scheme 1, serine, threonine, beta-hydroxyvaline and related derivatives are converted to the corresponding N-(4-substituted-benzenesulfonyl) derivatives 3 and alkylated with suitable substituted or unsubstituted 2-nitrobenzyl bromides or 2-nitrobenzyl chlorides to provide the corresponding nitro derivatives 5 . 15 Reduction under conventional reducing conditions, such as catalytic hydrogeneration (with Pd/C) or chemical reduction (e.g., with SnC1 2 or FeCl 3 ) results in amino derivatives 6. Reaction of the N- (2-aminobenzyl) derivatives 6 with alkanoyl chlorides, alkylsulfonyl chlorides, aroyl chlorides, heteroaroyl chlorides, aryl sulfonyl chlorides, heteroarylsulfonyl chlorides and the like, in the presence of trialkylamines or 20 pyridene, provides the dihydroalanine derivatives 7. Ring closure to the [1,4]benzodiazepine compounds 9 is carried out by reaction with a mild base such as sodium or potassium bicarbonate in an alcohol solvent such as methanol or ethanol. Standard conditions which involve hydrolysis of the ester (NaOH), acid chloride formation and reaction of the acid chloride with hydroxylamine are then used to convert 25 the ester derivatives 8 to the hydroxamic acids 9. Ester derivatives 8 (where the ester function is a t-butyl ester) are converted to the acid with trifluoroacetic acid under standard conditions. As illustrated in Reaction Scheme 2, derivatives 10, which contain a blocked hydroxyl group, are alkylated with 2-nitro or 2-amino benzyl alcohol derivatives 11 by 30 application of the Mitsunobu reaction to give intermediates 12. Reduction of the 2-nitro group and removal of the hydroxy blocking group with derivatives 12, where the R4 group is a protected amino moiety with simultaneous deblocking of the amino and hydroxyl functions, gives intermediate compounds 13. The intermediate 13 may then be reacted with benzyloxycarbonyl chloride to give the closed ring [1,4] benzodiazepine 35 14. Reaction of this compound with acyl chlorides, aroyl chlorides, heteroaroyl chlorides, alkysulfonyl chlorides, arylsulfonyl chlorides and heteroarylsulfonyl chlorides and the like results in the intermediates 15.

WO 99/37625 PCTIUS99/01325 - 16 0 Scheme 1

CH

3 0OC N 2 024 CSO R4-D I I I _R CH 3 0C NH + 2O

NOR

2 + 2HO RI N CH Br

CH

3 0C N4 HO I 'H R 0 soR \ 2 II 1

-~---CH

3 0C N HO R,

NO

2 Ar 2 tCOC1 Heteroaryl(CH 2 ).COCI5 R Ar(CH 2 )nSO 2 CI Heteroaryl(CH 2 )nso 2 c1 A~k1-OCH~On Alkyl-O-(CH 2 )SO 2 C1 '

O

2 Q-R AIkyTCOCI AlkyIS0 2 CI

CH

3 0C ~.R Cycloalkyl( C3to C 7 )CO R 1 9 SO J/Q 4

R

3 I1 Base8

CH

3 0 C I(1) OH )(2) CICOCOCI

R

1

R

2 HN/> R 4(3) NH 2 0H I I I 2

~QR

4 7 ~HOHN,>'No 9 wherein n = 0 to 3; 5 m=lIto 3; R,= (C 1 - C 3 )alkyl; R =Hydrogen; halogen; OCH 3 ; NO 2 ; NH 2 ; CF 3 ; NHCOCH 3 ;

NHCOCH

2

OCH

3 ; CONH 2 ; -N(R')(R'), -N(R')CO(C 1 - C 3 )alkyl; (C 1 - C 3 )alkyl; R= Ar(CH 2 )nCO-; HeteroaryI(CH 2 )nCO-, Ar(CH 2 )nSO 2 -; Heteroaryl(CH 2 )nSO 2 -; Alky1-O-CH 2 )nCO-; AlkybO-(CH 2 )mSO 2 -; AlkylCO-:, AlkylSO 2 -; AlkylCO 10 NHCH 2 CO-; and cycloalkyl(C 3 - C 7 )CO-; and

R

4 is as defined herein.

WO 99/37625 PCT/US99/01325 - 17 Scheme 2 o~s RO~\14 + ~ CO%-NH I I I H C30

CH

3 0C " NH IR HO + Q ( O*cJ.CH 20H 2 + 3 10 R 11

R

5 = -NO 2 t-BocNH- 3 P + DEAD 0 SO-{~R 4 R = OCH 2OCONH- 0-QR I I 1(1) H 2 P/ CH OC N

CH

3 OC N(2) H+ HO R R 5 t-BocNH VO0 13 (1)H + ; TFA 12 13~ ~ R R= CH 2 OCONH- 2 4/CH 2 OCOCI (1) H

R

6 COCR 0 SO 2

-(-\R

4 or0 SO , 11 or 11 CH30 C N R 7 S0 2 C1 CH30C N RR R 6 COCI R'N /.

R

2 NH 2 1 orR8 14 R 7 SO 2 CI 15 wherein nl = 0 to 3; m= I to3; 5 0 =phenyl; DEAD = diethylazodicarboxylate; R= Ar(CH 2 )n-; Alkyl-; Heteroaryl(CH2)n-;Alky1-O-(CH2)n-; Cycloalkyl(C 3

-C

7 );

R

7 = Ar(CH 2 )n-; Alkyl-; Heteroary1(CH 2 )n-; Alkyl-O-(CH2)m-;g

R

8 = Ar(CH 2 )nCO-; Ar(CH 2 )nSO 2 -; AlkylCO-; AlkylSO 2 -; Heteroary1(CH2)nCO-; 10 Heteroaryl(CH2)nS0 2 -; Alkyl-O-(CH 2 )nCO-; Alky1-O-(CH 2 )mSO 2

-.

WO 99/37625 PCT/US99/01325 - 18 1-substituted arylmethyl-2,3,4,5-tetrahydro- 1H [ 1.4]-benzodiazepines may be prepared in the manner illustrated in Reaction Schemes 3 and 4. In Reaction Scheme 3, the methyl 3-hydroxy-2-[4-methoxybenzenesulfonyl)-(2-aminobenzyl)amino] propionates 6 are subjected to reductive alkylation with arylcarboxaldehydes and 5 heteroarylcarboxaldehydes to provide intermediates 17. Standard reaction conditions such as reactions with triphenylphosphine and diethyl azodicarboxylate (DEAD) or triplenylphosphine with either carbon tetrachloride or carbon tetrabromide, results in the "dehydroalanine" derivatives 18 which are then ring closed to the [1,4]benzodiazepines 20. 10 In an alternative route to the 3-hydroxamic acid derivatives 21(Scheme 4), N aroyl derivatives 22 are reduced with reducing agents such as borane or lithium aluminum hydride to reduce both the ester and amide functions. The 3 (hydroxymethyl)- I-(arylmethyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine 23 are 15 oxidized with stardard reagents known to convert a hydroxymethyl group to a carboxylic acid:reagents such as NaIO4 with catalyst RuO2 (e.g., see J. Org. Chem., 46:3936 (1981); Synlett, p. 143, (1996)). Coupling the acids (via the acid chlorides) to hydroxylamine then gives products 21. Certain intermediates as exemplified by formula 25 may be reduced with borane under mild conditions to give derivatives 25a in 20 which the amide carbonyl is selectively reduced. These intermediates 25a are then converted to hydroxamic acid derivatives via hydrolysis of the ester to the acid and coupling the acid chloride with hydroxylamine.

WO 99/37625 PCT/UJS99/01325 - 19 Scheme 3 II? SO 9 ~ R 4 CH OC N CH 3 0C N ArCHO 30r R >1HO R H R

R

2 H 52P II 2 6 16 CH"Ar SNaCNBH 3 IHOAc S O 2 Q- R 4

CH

3 0C~ N- -" R (C 6

H

5

)

3 p CH~ Nl12 RIJ R, HN'N

CH

3 0C,,_- NR CH2Ar HOHR2 r 18 so 2

~~R

4 17 HA CH 3 OC_,N R (CH )p I I R e (C 4 ) CH 3 O0C .. N o R R H2A R2 N 201 wherein21 CH2Ar A r r rl Rio N N 0 or Ng R 9 s 0s fi.-RIO ; and Rgand R loare: Cl, Br, F, OCH 3 OEt , SCH 3

GG

3 COEt, CF 3 , OCF 3

,CNH

2 ,-NHCOCH 3 ,'or Me2N-.

WO 99/37625 PCT/US99/01325 - 20 Scheme 4

CH

3 0 R BH3 HOCH2"R N

BH

3 R R R N R N O -Ar

CH

2 Ar 22 23 O sof R 4 0 O Q R4 CHRr

R

2 N I R -iN/ CH -rHA ICHAr 21a 24 wherein Ro R9 R Ar= - R9 O R 9 -R or R9 R 6 I Ri o , and R 9 and Rio are hydrogen ,CI, Br, F, OCH 3 , OEt , o

SCH

3 ' COCH 3 , COEt, CF 3 , OCF 3 , or Me 2 N-. O 2 O R 4 SO 2o R4 CH30C CH 3 C N R4R BH 3 ~ RR R2 2 O '

R

8

CH

2

R

8 25 25a wherein R 8 = alkyl, arylalkyl, aryloxyalkyl, heterocyclicalkyl, or alkyloxyalkyloxyalkyl. 5 WO 99/37625 PCT/US99/01325 -21 Other, preferred compounds of the present invention are those with basic moieties in the 1-(substituted carbonyl) group which may be prepared in the manner shown in Reaction Scheme 5. Reaction of the 2,3,4,5-tetrahydro-lH-[1,4] benzodiazepines 14 (without a substituent at the 1-position) with carbonyl chloride 5 derivatives in the manner depicted in Reaction Scheme 5, results in intermediates 25 which are then converted to acid 26 and hydroxamic acids 27. The intermediates 25 may also be synthesized by reaction of methyl 2-[(2-aminobenzyl)-(4 methoxybenzenesulfonyl) amino]-3-hydroxypropionates 6 with acid chlorides to give "dehydroalanine" derivatives 28. As previously described, mild bases such as 10 NaHCO3 can be reacted with these derivatives to cause ring closure via a 1,4-addition to the double bond in intermediate 28 to provide the 7-membered 2,3,4,5-tetrahydro IH-[I,4] diazepines 25.

WO 99/37625 PCT/US99/01325 - 22 Scheme 5 SO 2 R 4 SO2 R4 CH30C NR. CH30C N RI> R 8COC RI / R R N R 2 H Et 3 N or pyridine 2 R 14 O 8 /'-1 25 Wherein

R

8 = O N-(CH2 (CH2)

OH

S N-(CH2)n N -(CH2 ) /1" N=/ 2 n CH

-(CH

2 )- O

N-(CH

2 )"

CH

3 O -(CH2) [ CH 3

(

C H 2) n 12N(CH2)n 0O t-Bo4N N -(CH 2 ) - II O n EtOC- N N -(CH2) CH20 -

CH

3

CONH

and n =0 to 3 S 2 R4 S02 R 4 HO N J HOC N R R O R8 O L R8 27 26 27 S0 2a R4 SO2 R 4

CH

3 OC N

CH

3 C N R2R R 8COCI RIR 2 H/ R HOXR" ( H R, Et 3 N O R8 6 28 NaHCO3 CH OH SO2,\) R4

CH

3 OCI R I YR 2N O

R

8 25 WO 99/37625 PCT/US99/01325 - 23 As illustrated in Reaction Scheme 6, aryl-arylcarbonyl, heteroaryl-arylcarbonyl, 5 aryl-heteroarylcarbonyl, heteroaryl-heteroarylcarbonyl derivatives 30 may be synthesized by standard palladium catalysed coupling of bromoaroyl or bromheteroaroyl derivatives 29 with appropriate arylstannanes, heteroarylstannanes, arylboronic acids, heteroarylboronic acids, aryl triflates, heteroaryl triflates and the like, under known conditions. For example, see Synthesis, 563-566 (1997); J. Org. 10 Chem., 62:3405-3406, (1997); Tetrahedron Lett.. 36:5247-5250, (1995); Heterocycles, 45:467, (1997); Tetrahedron Lett., 38:1118-1182, (1997); Heterocycles, 42:189-194, (1996); Tetrahedron Lett., 5005-5006, (1993); Synthesis, 843, (1987); Heterocycles, 2711-2716, (1987); and Tetrahedron Lett., 4407-4410, (1986). 15 By coupling with such palladium catalysts, aryl-aryl, heteroaryl-aryl, aryl heteroaryl and heteroaryl-heteroaryl carboxylic ester derivatives can be prepared and these derivatives converted to carboxylic acid intermediates. The acids are then converted to acid chlorides which are reacted with esters of 2- [(2-aminobenzyl)-(4 substituted-benzenesulfonyl)amino]-3-hydroxypropionate as illustrated for conversion 20 of derivatives 6 to intermediates 31. The following references describe procedures for the synthesis of methyl 3-arylpyrrole-4-carboxylates as in J. Org. Chem.. 62:2649 2651, (1997); methyl (2-methylphenyl) benzoates as in J. Org. Chem., 62:3405-3406, (1997); and methyl benzoates substitued with heterocyclic moieties such as furanyl, thienyl or pyridinyl groups as in Tetrahedron Lett., 27:4407-4410, (1986). 25 WO 99/37625 PCT/US99/01325 - 24 Scheme 6 0O R4 0

-\)R

4 CHOC N \(K~ C R Y W ; ;or Yetc R-t /~ Y N -- 7 2 etc IIRNb2 BO n S S4- W= B(OH) 2 ; SnMe 3 ; Sn(n-butyl) 3 Ar' O9 AO-Triflate; ZnC1 ; or ZnBr; 29 Br irIr Ar'= , , or O 2 / N S 0 t fa R Br CH- 3 0C HI Pd(PPh 3

)

4 or Pd(PPh 3

)

2 C1 2 HH R or R, R 2 H, equivalent Pd catalyst 6 ' SO2 R4 0SO 26R4 O

CH

3 OC N CH 3 0 RR R Et3N +or

R/-,

N R Ror R2 I 2 ' H- r" CI O Ar" Ar" 30 31 o Ar" M M M Y

I-

where Ar" =.- M L M X Y L is CONH- CONH- , ,or ~ CONH M i s YY Y N N'N, r Y N I i0 N R' R' Y is H, F, Cl, CF 3 , CH 3 , or OCH 3 ; X is halogen, hydrogen, or (C 1 - C 3 )alkyl; 5 R and R' are as defined herein; and

R

4 is as defined herein.

WO 99/37625 PCT/US99/01325 - 25 The intermediates 2.4,5.6-tetrahydro-IH-[1.4]benzodiazepines 39 and 38 may be prepared from glycine esters in the manner exemplified in Reaction Scheme 7. In this synthetic route, N-(4-substituted-benzenesulfonyl) derivatives of glycine ethyl 5 ester, glycine t-butyl ester or glycine methyl ester 33 are alkylated with a substituted (R) or unsubstituted (R=H) 2-nitrobenzyl bromide in N.N-dimethylformamide or 1-methyl 2-pyrrolidinone in the presence of potassium carbonate to give intermediates 34. Alternatively, the esters of N-(4-substituted-benzenesulfonyl) glycines. such as the methyl ester 33. are first reacted with sodium hydride in N. N-dimethylformamide or 1 10 methyl-2-pyrrolidinone and the resulting anion reacted with substituted or unsubstituted 2-nitrobenzylbromides to provide compounds 34. Reaction of derivates 34 with N,N dimethyl(methylene)ammonium chloride or the iodide salts under standard reaction conditions (e.g., as set forth in Fieser and Fieser, 10:160-161; 8:194 affords the dimethylaminomethyl (Mannich type) compounds as intermediates for elimination to the 15 "dehydroalanine" derivatives 37 or direct ring closure of 36 to 39 via an elimination addition reaction. Ring closure of compounds 37 provides intermediates 38 for conversion to hydroxamic acids. Variations of the reactions conditions for conversion of 36 to 39 involve heating in the presence of Lewis acids, such as BF3, or heating an acid salt of 36 to effect the elimination-addition reaction.

WO 99/37625 PCT/US99/01325 - 26 Scheme 7 0 0 CHr 3

OCCH

2

NH

2 + C1O 2

Q~

4

H

3

OCH

2 NHOcQ-R 4 32 2 & C 2 B 0 X R

CH

3

OCCH

9 INl-S0 - R0

CH

2 11

SNH

2 Ht CH 3 OCCH7 N-SO 2 - R PdCil

CH

2 N2 + R orCH, = N(CH 3

)

2 C1- 3

CH

2 = N(CH 3

)

2 1 0 R 11-G- 0 Sol

CH

3 OCCH- N- SO2- R411 1

(CH

3

)

2

N-CH

2 U1 2 \p. HN / NH2 k3 36 37 0 V0 4Y 0& R

CH

3 OCI \~ R R 39 38 5 WO 99/37625 PCT/US99/01325 - 27 The intermediate carboxylic acids for conversion to the tetrahydro[1,4]benzodiazepine-3-carboxylic acid, hydroxyamides may be synthesized via different routes as shown in Schemes 1-8. For the synthesis of some of the desired products of Formula 1, alternate routes may be preferred as shown in Scheme 8. 5 Under these conditions, intermediate carboxylate esters of Intermediate 41 or acids of Intermediate 44 wherein the R 4 substituent is an OH group are prepared. Intermediates with R 4 an OH group may be prepared from derivatives wherein the OH group is protected by a group which can be selectively removed. Derivatives 40 wherein R 4 is an OCH 3 moiety are suitable precursors to the desired phenolic compounds 41 and 44 10 through cleavage of the oxygen methyl bond. As shown in Scheme 8, the anion of the phenolic OH group may be prepared in situ and then alkylated. Suitable bases are alkaline metal carbonates, hydrides, alkoxides and organic bases. Reaction with an alkylating moiety represented by the Formula (C,-C 6 )alkyl-X wherein X is a reactive leaving group such as a chloride, bromide, iodide, O-mesylate of an O-tosylate gives 15 the derivatives 42 and 45. The alkylation reaction may be carried out with caboxylate esters such as 41 or with the carboxylic acids such as 44. Alternatively, the phenolic compounds 41 and 44 may be reacted under Mitsunobe Reaction conditions to afford the O-alkylated 20 derivatives 42 and 45. Standard Mitsunobe Reaction conditions, such as those described in the following literature references, may be used in the coupling reactions: J. Heterocyclic Chem. 34:349 (1997); Tetrahedron Lett. 37:6439 (1996); J. Org. Chem., 56:7173 (1991); Tetrahedron Lett. 5709 (1989); Synthesis 1:28 (1981).

WO 99/37625 PCTIUS99/0132S - 28 Scheme 8 O 07 -OI1 0 o 2 -QOH

CH

3 0O BBr 3

CH

3 0O 40

(CI-C

6 )alkyl-X 41 O )OH- Base or (C 1

-C

6 )alkylOH 2)Br (CAH P 2)B~I DEAD N S0- O 0 O~9 0O-alkyl(C 1

-C

6 ) HOR

I

2

CH

3 O/2 R 443R2R

(C

6

H

5

)

3 P 42 or Base DEAD (C 1 -C,)alkyIOH

(C

1

-C

6 )alkyl-X IOH O §02 O-alkyl(C 1

-C

6 ) o SO 2 -Q--O-alkyl(C 1

-C

6 )

(C

1

-

6 )alkylqR OH NObR RIR 45 43

(C

1

-C

6 )alkyl-X X= halogen, OTs, OMs WO 99/37625 PCT/US99/01325 - 29 The compounds of the present invention which have a basic moiety may be used in the form of salts derived from pharmaceutically or physiologically acceptable acids. 5 These salts include, but are not limited to, salts with inorganic acids (such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid) or organic acids (such as acetic acid, oxalic acid, succinic acid, and maleic acid). Other salts of compounds with an acidic moiety include those with alkali metals or alkaline earth metals (such as sodium, potassium, calcium, and magnesium) or organic bases. 10 When the present compounds are utilized in pharmaceutical compositions, they may be combined with one or more pharmaceutically acceptable carriers, e.g., solvents, diluents and the like. Such compositions containing the present compounds may be administered orally, in the form of tablets, capsules, dispersible powders, granules, 15 suspensions, syrups or elixirs; parentally, in the form of a sterile injectable solution or suspension; or topically, in the form of creams, lotions, ointments, etc. Such pharmaceutical compositions may contain from about 1 to about 100 mg of active ingredient in combination with the carrier. 20 The effective dosage of the present compounds utilized to treat a specific condition will vary depending upon the particular compound employed, the mode of administration and the type and severity of the condition being treated. However, in general, satisfactory results are obtained when the present compounds are administered at a dosage of about 0.001 to 1000 mg/kg of body weight. 25 As noted above, the compounds of the present invention may be administered orally, as well as by intravenous, intramuscular, subcutaneous or topical routes. Solid carriers useful for preparing tablets, capsules, etc., include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin. Liquid carriers useful for 30 preparing compositions of the present compounds include sterile water, polyethylene, glycols, non-ionic surfactants, and edible oils such as corn, sesame, and peanut oils. Adjuvants conventionally used in the preparation of pharmaceutical compositions may also be included, such as flavoring agents, coloring agents, preservatives and antioxidants. 35 The compounds of the present invention were tested for biological activity according to the following procedures.

WO 99/37625 PCT/US99/01325 - 30 In Vitro Gelatinase Assay The assay is based on the cleavage of the thiopeptide substrate ((Ac-Pro-Leu 5 Gly(2-mercapto-4-methyl-pentanoyl)-Leu-Gly-OEt), available from Bachem Bioscience) by the enzyme gelatinase, releasing the substrate product which reacts colorimetrically with DTNB ((5,5'-dithio-bis(2-nitro-benzoic acid)). This assay is disclosed in Weingarten et al., "Spectrophotometric Assay for Vertebrate Collegenase", Anal. Biochem., 147:437-440, (1985). The enzyme activity is measured by the rate of 10 the color increase. The thiopeptide substrate was made up fresh as a 20 mM stock in 100% DMSO and the DTNB was dissolved in 100% DMSO as a 100 mM stock and stored in the dark at room temperature. The substrate and the DTNB were diluted together to 1 mM with 15 substrate buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2) before use. The stock of human neutrophil gelatinase B was diluted with assay buffer (50 mM HEPES, pH 7.5, 5 mM CaCl2, 0.02% Brij) to a final concentration of 0.15 nM. The assay buffer, enzyme, DTNB/substrate (500 pM final concentration) and 20 vehicle or inhibitor were added to a 96 well plate (total reaction volume of 200pI) and the increase in color was monitored spectrophotometrically for 5 minutes at 405 nm on a plate reader. The increase in OD405 was plotted and the slope of the line was calculated. The 25 slope represents the reaction rate. The linearity of the reaction rate was confirmed (r 2 >0.85) and the mean (x ± sem) of the control rate was calculated and compared for statistical significance (p <0.05) with drug-treated rates using Dunnett's multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression (IPRED, 30 HTB). In Vitro Collagenase Assay This assay was based on the cleavage of a peptide substrate ((Dnp-Pro-Cha 35 Gly-Cys(Me)-His-Ala-Lys(NMa)-NH2), available from Peptide International, Inc.) by collagenase releasing the fluorescent NMa group which was quantitated on the fluorometer as disclosed in Bickett et al., "A High Throughput Fluorogenic Substrate WO 99/37625 PCT/US99/01325 -31 for Interstitial Collagenase (MMP-1) and Gelatinase (MMP-9)", Anal. Biochem., 212:58-64, (1993). Dnp quenches the NMa fluorescence in the intact substrate. The assay was run in HCBC assay buffer (50 mM HEPES, pH 7.0, 5 mM 5 Ca + 2 , 0.02% Brij, 0.5% Cysteine), with human recombinant fibroblast collagenase (truncated, mw=18,828, from Wyeth-Ayerst Research, Radnor, PA). The substrate was dissolved in methanol and stored frozen in 1 mM aliquots. Collagenase was stored frozen in buffer in 25 pM aliquots. In conducting the assay, the substrate was dissolved in HCBC buffer to a final concentration of 10 pM and collagenase to a final 10 concentration of 5 nM. The compounds being examined were dissolved in methanol, DMSO, or HCBC. The methanol and DMSO were diluted in HCBC to < 1.0%. The compounds were added to a 96 well plate containing enzyme and the reaction was started by the addition of substrate. 15 The reaction was read (excitation 340 nm, emission 444 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line was calculated representing the reaction rate. The linearity of the reaction rate was confirmed (r 2 >0.85). The mean (x ± sem) of the control rate was calculated and compared for statistical significance (p <0.05) with drug-treated rates using Dunnett's 20 multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression. Procedure for Measuring TACE Inhibition 25 In a 96-well black microtiter plate, each well received a solution composed of 10 pL TACE (available from Immunex) at a final concentration of I pg/mL, 70pL Tris buffer, have a pH of 7.4 and containing 10% glycerol (final concentration 10 mM), and 10 pL of test compound solution in DMSO (final concentration I pM, DMSO concentration <1%). The plates were incubated for 10 minutes at room temperature. 30 The reaction was initiated by addition of a fluorescent peptidyl substrate (final concentration 100 pM) to each well with shaking on a shaker for 5 sec. The reaction was read (excitation 340 nm, emission 420 nm) for 10 min. and the increase in fluorescence over time was plotted as a linear line. The slope of the line 35 was calculated and this represents the reaction rate. The linearity of the reaction rate was confirmed (r 2 >0.85). The mean (x±sem) of the control rate was calculated and compared for statistical significance (p<0.05) with drug-treated rates using Dunnett's WO 99/37625 PCT/US99/01325 - 32 multiple comparison test. Dose-response relationships were generated using multiple doses of drug and IC50 values with 95% CI were estimated using linear regression. The results obtained following these standard experimental test procedures are 5 presented in Table 1. Table 1 O O2 -R 4 HOHNR R2 R3 R3 Compound of R3 Example R R 1

R

2

R

4

IC

50 (nM) MMP-1 MMP-9 MMP-13 TACE

-SO

2

CH

3 2 H H H -OCH 3 _ 14.1 5.1 391 t 12

-SO

2

CH

3 3 H H H -OCH 3 156.5 7.9 3.0 104 t 8

-SO

2

CH

2

CH

2

CH

3 10 H H H -OCH 3 183 7.0 2.8 91 ± 10 -SO0 -OCH 3 4 H H H -OCH 3 224.1 12.2 4.3 101 _ 3

-COCH

3 6 H H H -OCH 3 18.4 1.4 1.0 103- 7 -COO 5 H H H -OCH 3 15.8(23) 0.56(1.7) 0.4 (1.1) 95 + 10 WO 99/37625 PCT/US99/01325 - 33 Compound of

R

3 Example R R, R 2 R4 IC 50 (nM) MMP-1 MMP-9 MMP-13 TACE -CO- N 7 H H H -OCH 3 20.4 (34) 0.6 (1.9) 0.4 (1.3) 77.7 + 7 -CO- 8 H H H -OCH 3 19.7 1.1 1.1 12.8 t 1.2 -CO- N 13 H H H -OCH 3 54.9 9.8 2.0 154 + 27

COCH

2

OCH

3 9 H H H -OCH 3 34.1 1.34 1.19 95.2 + 14.8 -CO(CH 2)2 12 H H H -OCH 3 523 17.9 25.7 207 + 21 -CO 1 H H H -OCH 3 96.2 5.1 3.7 352 34

CF

3

CH

3 -CO 11 H H H -OCH 3 55.4 3.9 2.3 271 1 20 F -C&O 15 H H H -OCH 3 52.7 0.7 0.4 199 + 19 -C 14 H H H -OCH 3 542 12.6 3.7 45% (luM) -COA 55 H H H -OCH 3 171 4.0 3.3 68.5 ± 7.2 -CO 57 H H H -OCH 3 465 12.7 7.2 318 1 27 -CO-Q Cl 31 H H H -OCH 3 75.5 3.0 2.6 36%(IuM) Cl -CO 40 H H H -OCH 3 16.6 1.4 1.2 28.5 + 6.6 0 -COCH 2 oC 58 H H H -OCH 3 65.5 4.4 2.9 154 + 20 5 WO 99/37625 PCT/US99/01325 - 34 Compound of

R

3 Example R R 1 R_ R 4

IC

50 so (nM) - - - MMP-1 MMP-9 MMP-13 TACE

-COCHOCH

3 59 7-CH H H -OCH 3 105 2.6 1.8 125 + 6 -CO 60 7-CH 3 H H -OCH 3 22.7 1.4 1.3 143 + 4 -CO( -OCF 3 61 8-Cl H H -OCH 3 239 (265) 1.3 (3.9) 0.4 (4.3) 1248 + 69 -CH2CH 2

OCH

3 62 H H H -OCH 3 1000 100 100 51 (lIM) 63 7-CH 3 H H -OCH 3 130 5.6 3.1 446 +48 64 8-Cl H H -OCH 3 157 6.1 3.4 384 + 8

-CO

-CO-- -OC 2

H

5 65 H H H -OCH 3 23.5 1.5 1.5 157 + 13 Cl -CO NCH 3 66 H H H -OCH 3 83.4 3.4 2.6 148+ 14 -CH2- 67 H H H -OCH 3 1323 50.8 73.9 551 + 29

CH

3 0 -CO t 71 H H H -OCH 3 41.3 2.4 1.3 136+ 15

OCH

3

-CO-CHT--N.N-CH

3 72 H H H -OCH 3 4982 187 317 808 +90 The present invention will now be illustrated with reference to the following, 5 non-limiting examples. Reference Example 1 (L) N-(Benzyloxycarbonyl)-O-benzylserine, t-butyl ester Into a solution of 25 g (0.076 mol) of N-(benzyloxycarbonyl)-O-benzylserine in 10 600 ml of CH2C12 cooled to -6oC in an ice-salt bath was bubbled isobutylene, while 4.1 ml of concentrated sulfuric acid was added dropwise thereto. The mixture was stirred for 4 hours and worked up as described in Synthetic Commun., 26:2723 (1996) to give 29.24 g of product as a yellow oil.

WO 99/37625 PCT/US99/01325 - 35 Reference Example 2 L-Serine, t-butyl ester A mixture of 29.24 g (0.076 mol) of (L) N-(benzyloxycarbonyl)-O benzylserine, t-butyl ester from Reference Example 1, 24.1 g (0.38 mol) of ammonium 5 formate and 38.3 g of 10% palladium on carbon in 600 ml of methanol was heated at 65oC for 20 hours and stirred at room temperature overnight. The mixture was filtered through diatomaceous earth and the filter pad was washed with methanol. The filtrate was concentrated to give 12.18 g (99.6%) of product as described in Synthetic Commun., 26:2723 (1996). 10 Reference Example 3 N-(4-Methoxybenzenesulfonyl)-L-serine, t-butyl ester (3-hydroxy-2-(4 methoxybenzenesulfonylamino)propionic acid, tert-butyl ester) To a solution of 12.18 g (0.0756 mol) of L-serine, t-butyl ester, 26.52 ml of 15 triethylamine in 160 ml of CH2Cl2 (cooled in an ice bath) was added, in small portions, 16.1 g (0.0771 mol) of 4-methoxybenzene-sulfonyl chloride. The mixture was stirred at 0 0 C for 0.5 hours and at room temperature overnight. The mixture was washed with H20, 2N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 25.34 g of solid which was triturated with hexane. The solid was 20 recrystallized from 120 ml of toluene to give 12.18 g (48.7%) of product as a white solid. The filtrate was concentrated and the residue chromatographed on silica gel with hexane-ethyl acetate (7:3) as eluent to give 5.71 g (22.8%) of white solid. m.p. 70 75 0 C. Anal. for C14H21NO6S: Calc'd: C, 50.7; H,6.4; N,4.2; 25 Found: C, 50.4; H,6.3; N,4.4. Reference Example 4 3-Hy d roxy-2-[(4-methoxybenzenesul Ifonyl)-(2-nitrobenzyl)amino] propionic acid, tert-butyl ester 30 To 6.16 g (18.6 mmol) of 3-hydroxy-2-(4-methoxybenzenesulfonylamino) propionic acid tert-butyl ester in 50 ml of N,N-dimethylformamide, cooled in an ice bath, was added 0.781 g (19.5 mmol) of sodium hydride. After gas evolution ceased, a solution of 4.02 g (18.6 mmol) of 2-nitrobenzylbromide in 18 ml of N,N dimethylformamide was added dropwise. The mixture was stirred under nitrogen at 35 room temperature for 4 hours and 1.0 g of 2-nitrobenzyl bromide was added. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was diluted with water and extracted with CH2C12. The organic WO 99/37625 PCT/US99/01325 - 36 extract was washed with H20, brine and dried with Na2SO4. The solvent was removed to give 11.2 g of solid which was chromatographed on silica gel with hexane ethyl acetate (1:1) as eluent followed by hexane-ethyl acetate (35:65) as eluent. The fractions containing product were combined and the solvent was then removed to gave 5 7.7 g (89%) of solid. A sample from a 3 mmol run gave a gum. Anal. for C21H26N208S: Calc'd: C,54.1; H,5.6; N,6.0; Found: C,54.0; H,5.7; N,6.0. 10 Reference Example 5 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3 hydroxypropionic acid, tert-butyl ester A mixture of 0.60 g (1.28 mmol) of 3-hydroxy-2-[(4-methoxybenzene sulfonyl)-(2-nitrobenzyl)amino] propionic acid, tert-butyl ester and 1.45 g (6.45 mmol) 15 of SnCl2*2H20 in 20 ml of methanol was heated in an oil bath at 90'C for 2 hours. The solvent was removed under vacuum and ethyl acetate added to the residue. The mixture was neutralized with saturated sodium bicarbonate solution and filtered through diatomaceous earth. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2SO4. The solvent was removed under vacuum to give 0.30 g (53%) 20 of a gum. Anal. for C21H28N206S: Calc'd: C, 57.8; H,6.5; N,6.4; Found: C, 57.8; H,7.0; N,6.2. Reference Example 6 25 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3 hydroxypropionic acid A solution of 0.75 g (1.72 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzene sulfonyl)amino]-3-hydroxypropionic acid, tert-butyl ester and 6 ml of trifluoroacetic acid in 6 ml of CH2Cl2 was stirred at room temperature for 3 hours and then 30 concentrated to dryness under vacuum. To the residue was added H20, CH2CI2 and IN NaOH until the aqueous layer reached pH 8. The aqueous layer was then separated, acidified with 2 N citric acid and extracted with ethyl acetate. The extract was washed with H20, brine and dried Na2SO4. The solvent was removed under vacuum to give 0.35 g (54%) of a solid. Anal. for Cl7H20N206S: 35 Calc'd: C, 53.7: H,5.3; N,7.4; Found: C, 53.0; H,5.3; N,6.9.

WO 99/37625 PCT/UJS99/01325 - 37 Reference Example 7 2-{1(2-[3-(Trifluoromethylbenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylic acid, tert-butyl ester A mixture of 0.431 g (1 mmol) of 2 -[(2-amino-benzyl)-(4-methoxybenzene 5 sulfonyl)amino]-3-hydroxy-propionic acid, tert-butyl ester, 0.474 g (2.2 mmol) of 3 (trifluoromethyl)benzoyl chloride and 1 ml of pyridine in 2 ml of CH2Cl2 was stirred at room temperature for 3.5 hours. The mixture was poured into H20 and extracted with CH2Cl2. The extract was washed with H20, 2 N citric acid, H20. 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed to give 0.72 g of solid. The 10 solid was dissolved in 2 ml of tetrahydrofuran and 1.5 ml of triethylamine was added thereto. The solution was heated at 65oC overnight and concentrated to dryness under vacuum. The residue was extracted with CH2C12 and the extract washed with H20 and dried with Na2SO4. The solvent was removed under vacuum to give 0.55 g of product as a solid. From a similar run the product was chromatographed on silica gel 15 with hexane-ethyl acetate to give a solid, m.p. 65-72oC. Anal. for C29H29F3N206S: Calc'd: C, 59.0; H,5.0; N,4.7; Found: C, 59.2; H,5.2; N,4.4. Reference Example 8 20 4-(4-Methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester A mixture of 0.55 g (0.932 mmol) of 2-{(2-[3-(trifluoromethyl)benzoyl] aminobenzoyl]-(4-methoxybenzenesulfonyl)amnino} acrylic acid, tert-butyl ester and 0.102 g (1.21 mmol) of NaHCO3 in 4 ml of methanol was stirred at room temperature 25 overnight and the solvent removed. The residue was extracted with CH2Cl2 and the extract washed with H20, brine and dried with Na2SO4. The solvent was removed to give 0.57 g of solid. The solid was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.30 g of a light yellow solid, m.p. 57-60 0 C. Anal. for C29H29F3N206S: 30 Calc'd: C,59.0; H,5.0; N,4.7; Found: C,58.8; N,5.0; N,4.6.

WO 99/37625 PCT/US99/01325 - 38 Reference Example 9 4-(4-Methoxybenzenesulfonyl)-1- (3- t rifluoromethylbenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid A mixture of 0.36 g (0.61 mmol) of 4-(4-methoxybenzenesulfonyl)-1-(3 5 trifluoromethylbenzoyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylic acid, tert-butyl ester and 3 ml of trifluoroacetic acid in 3 ml of CH2Cl2 was stirred at room temperature for 3 hours. The mixture was concentrated to dryness under vacuum and the residue extracted with CH2Cl2. The CH2C12 was washed with 1 N NaHCO3 and the aqueous layer (pH 8) was acidified with 2 N citric acid and extracted with ethyl 10 acetate. The extract was dried (Na2SO4). The original CH2Cl2 extract was washed with 2 N citric acid, H20, brine and dried with Na2SO4. The CH2Cl2 extract and the ethyl acetate extract were combined and the solvent removed under vacuum to give 0.31 g of solid, m.p. 105-110C. Anal. for C25H21F3N206S: Calc'd: C,56.2; H,4.0; N,5.2; 15 Found: C,55.1; H,3.7; N,5.0. Reference Example 10 Methyl 1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate 20 To a mixture of 1.5 g (3.8 mmol) of methyl 2-[(2-aminobenzyl)-(4 methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.65 ml of triethylamine in 12 nml of CH2CI2 chilled at 0OC was added a solution of [1,1'-biphenyl]-2-carbonyl chloride in 6 ml of CH2Cl2. The mixture was stirred at room temperature overnight and diluted with CH2Cl2 and H20. The organic layer was separated and washed with 25 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C31H28N206S: Calc'd: C,66.9; H,5.1; N,5.0; Found: C,67.3; H,5.2;N,4.7. 30 Reference Example 11 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl) 2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylate To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4 methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.64 ml (18.97 mmol) of 35 triethylamine in 15 ml of CH2Cl2, chilled to 0OC, was added 1.36 g (11.4 mmol) of 2 methyl-5-fluorobenzoyl chloride. The mixture was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 and water and the organic layer WO 99/37625 PCT/US99/01325 - 39 separated. The organic layer was washed with 2 N citric acid. brine and dried with Na2SO4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C26H25FN206S: Calc'd: C,60.9; H,4.9; N,5.5; 5 Found: C,60.9; H,5.0; N,5.0; Mass spectrum (ES) 513.4 (M+H). Reference Example 12 Methyl 4-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4] 10 benzodiazepine- 3-carboxylate To a mixture of 5.0 g (12.68 mmol) of methyl 2-[(2-aminobenzyl)-(4 methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 17.7 ml (26.8 mmol) of triethylamine in 50 ml of CH2Cl2 chilled to 0 0 C was added 9.05 ml (63.4 nurnol) of benzyl chloroformate. The mixture was stirred overnight and then cooled to 0OC and .8 15 ml of triethylamine and 9.05 ml (63.4 mmol) of benzyl chloroformate were added thereto. The mixture was stirred overnight and then washed with H20, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 6.95 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (1:1) to give 2.7 g of product as a viscous yellow oil. From a similar 0.5 g run, there was 20 obtained 0.178 g of an oil. Anal. for C 1 8H20N205S: Calc'd: C,57.4; H,5.4; N,7.4; S,8.5; Found: C,57.9; H,5.4; N,6.7; S,7.9; Mass spectrum (ES) 377.2 (M+H). 25 Reference Example 13 Methyl 3-Hydroxy-2-(4-methoxybenzenesulfonylamino)propionate To a mixture of 5.0 g (32.14 mmol) of D,L-serine, methyl ester and 15.7 ml (0.012 mol) of triethylamine in 100 ml of CH2CI2, cooled to 0OC, was added portionwise 6.64 g (32.14 mmol) of 4-methoxybenzenesulfonyl chloride. The mixture 30 was then stirred under argon at room temperature for 2 days. The mixture was diluted with 100 ml of CH2CI2 and then washed with 60 ml each of H20, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a solid. Crystallization from ethyl acetate gave 5.0 g (54%) of white crystals, m.p. 92-94oC. Anal. for CllH15NO6S: 35 Calc'd: C,45.7; H,5.2; N,4.8; S,11.1; Found: C,45.6; H,5.2; N,4.8; S,11.1.

WO 99/37625 PCT/US99/01325 -40 Reference Example 14 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-nitrobenzyl) amino]propionate To a solution of 15.0 g (51.85 mmol) of methyl 3-hydroxy-2-(4 5 methoxybenzenesulfonylamino)propionate in 125 n-ml of N,N-dimethylformamide, cooled in an ice bath, was added portionwise 2.29 g (57.03 mmol) of NaH (60% in oil). The mixture was stirred at 0 0 C for 20 minutes and then a solution of 12.32 g (57.03 mmol) of 2-nitrobenzyl bromide in 25 ml of dry N,N-dimethylformamide was added dropwise. The solution was stirred at room temperature for 48 hours and diluted 10 with 500 ml of ethyl acetate and water. The organic layer was separated and the aqueous layer extracted with 250 ml of ethyl acetate. The combined organic layer and extract was washed with 200 ml each of H20, I N NaHCO3, brine and dried with Na2SO4. The solvent was removed and the residual solid was triturated with ethyl acetate, cooled and filtered to give 13.5 g (61%) of white crystals, having a m.p. 127 15 129 0 C. From a small scale run (3.0 g) there was obtained 2.32 g of white crystals, having a m.p. 127-129oC. Anal. for C18H20N208S: Calc'd: C,50.9; H,4.8; N,6.6; Found: C,50.9; H,4.8; N,6.5. 20 Reference Example 15 Methyl 2-[(2-Aminobenzyl)-(4-methoxybenzenesulfonyl)amino] 3-hydroxypropionate To a mixture under nitrogen of 1.5 g (3.53 mmol) of methyl 3-hydroxy-2-[(4 methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]propionate in 5 ml of dry ethanol was 25 added 1.12 g (17.69 mmol) of ammonium formate followed by the addition of 0.50 g of 10% palladium on carbon. The mixture was stirred overnight at room temperature and heated at 80 0 C for 2 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give a semisolid. Trituration with ethyl acetate gave 0.65 g (47%) of white crystals, m.p. 138-140oC; Anal. for 30 C18H22N206S: Calc'd: C,54.8; H,5.6; N,7.1; Found: C,53.0; H,5.6; N,6.8.

WO 99/37625 PCT/US99/01325 -41 Reference Example 16 Methyl 3-Hydroxy-2-{(4-methoxybenzenesulfonyl)-[2-(2,2,2 trifluoroacetylamino)benzy l]amino }propionate To a solution of 0.50 g (1.27 mmol) of methyl 2-[(2-aminobenzyl)-(4 5 methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 5 ml of CH2Cl2 was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride. The solution was stirred for 1 hour and concentrated to dryness under vacuum. Methanol was added to the residue and the solvent was removed under vacuum. The addition of methanol and concentration to dryness was repeated twice. The residue was chromatographed on silica gel thick layer 10 plates with hexane-ethyl acetate (1:1) to give 0.50 g of a colorless glass. Anal. for C20H21F3N207S: Calc'd: C,49.0; H,4.3; N,5.7; Found: C,49.0; H,4.5; N,5.4. 15 Reference Example 17 Methyl 2-[(4-Methoxybenzenesulfonyl)-(2-nitrobenzyl)amino] acrylate To a solution of 1.0 g (2.356 mmol) of methyl 3-hydroxy-2-[(4 methoxybenzenesulfonyl)-(2-nitrobenzyl) amino]propionate in 2 ml of pyridine, cooled 20 to -10C was added 0.539 g (2.83 mmol) of 4-methylbenzeuesulfonyl chloride. The solution was chilled overnight and 4 ml of pyridine and 0.539 g (2.83 mmol) of 4 methylbenzene-sulfonyl chloride were added. The mixture was stirred and chilled at -10 0 C for 24 hours and diluted with H20. The mixture was extracted with ethyl acetate and the extract washed with H20, 2 N citric acid, and brine and then dried (Na2SO4). 25 The solvent was removed under vacuum to give 1.2 g of an oil. The oil was dissolved in 6 ml of pyridine and 1.08 g of 4-methylbenzenesulfonyl chloride was added thereto. The mixture was stirred at room temperature overnight and diluted with H20. The mixture was extracted with ethyl acetate and the extract was washed with H20, 2 N citric acid, and brine and then dried with Na2SO4. The solvent was removed to give 30 1.0 g of brown oil. The oil was crystallized from ethanol to give white crystals, m.p. 65 67 0 C. Anal. for C18H18N207S: Calc'd: C,53.2; H,4.5; N,6.9; Found: C,53.7; H,4.5; N,7.2. 35 WO 99/37625 PCT/US99/01325 -42 Reference Example 18 Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(4-pyridinylcarbonyl) aminobenzyl]amino}acrylate To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4 5 methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 3.0 ml (21.6 mmol) of triethylamrnine in 15 ml of CH2Cl2, cooled to 0OC was added 1.7 g (9.5 mmol) ml of 4 pyridinecarbonyl chloride (isonicotinoyl chloride). The mixture was stirred at room temperature overnight and diluted with CH2CI2. The mixture was washed with H20, 2 N citric acid, and brine and then dried with Na2SO4. The solvent was removed to 10 give 1.8 g of a light tan solid; Anal. for C24H23N306S: Calc'd: C,59.9; H,4.8; N,8.7; S,6.6; Found: C,59.0; H,4.8; N,8.5; S,6.9; Mass spectrum (ES) 482.6(M+H). 15 Utilizing the procedure described in Reference Example 18. the following intermediate compounds can be prepared from the appropriately unsubstituted methyl 2 [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate or the appropriately substituted methyl 2-[(substituted-2-aminobenzyl)-(4-methoxybenzene sulfonyl)amino]-3-hydroxypropionate. 20 Reference Example 19 Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(2,2,2 trifluoroacetylamino)benzyl]amino}acrylate white crystals, m.p. 120-121 0 C. Anal. for C20H19F3N206S: 25 Calc'd: C,50.9; H,4.1; N,5.9; Found: C,50.8; H,4.2; N,5.6. Reference Example 20 Methyl 2-[(2-Benzoylaminobenzyl)-(4-methoxybenzenesulfonyl) 30 amino]acrylate yellow oil. Anal. for C25H24N206S: Calc'd: C,62.5; H,5.0; N,5.8; Found: C,62.7; H,5.3; N,5.0. 35 Reference Example 21 Methyl 2-[(2-Acetylaminobenzyl)-(4-methoxybenzenesulfonyl) amino]acrylate WO 99/37625 PCT/US99/01325 -43 Reference Example 22 Methyl 2-((4-Methoxybenzenesulfonyl)- {2-[(3 pyridinylcarbonyl)amino]benzyl }amino)acrylate 5 off-white solid. Anal. for C24H23N306S: Calc'd: C,59.9; H,4.8; N,8.7; S,6.6; Found: C,58.9: H,4.8; N,8.4; S,6.4; Mass spectrum (ES) 482.8(M+H). 10 Example 23 Methyl 2-((4-Methoxybenzenesulfonyl)-{ [(2 thienylcarbonyl)amino]benzyl}amino)acrylate tan solid. Anal. for C23H22N206S2: Calc'd: C,56.8; H,4.6: N,5.8; 15 Found: C,55.7; H,4.4; N,4.9. Reference Example 24 Methyl 2-{ [2-(-Methoxyacetylamino)benzyl]-(4 methoxybenzenesulfonyl)amino}acrylate 20 yellow oil. Anal. for C21H24N207S: Calc'd: C,56.2: H,5.4; N,6.3; Found: C,55.3; H,5.6; N,5.8. Reference Example 25 25 Methyl 2-{ (4-Methoxybenzenesulfonyl)-[2-(n propylsulfonylamino)benzyl]amino}acrylate light brown oil. Anal. for C21H26N207S2: Calc'd: C,52.3; H,5.4; N,5.8; Found: C,51.9; H,5.4; N,5.7. 30 Reference Example 26 Methyl 2-{ [2-(3-Phenylpropionyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate light brown oil. Anal. for C27H28N206S: 35 Calc'd: C,63.8; H,5.6; N,5.5; Found: C,66.7; H,5.8; N,4.1.

WO 99/37625 PCT/US99/01325 - 44 Reference Example 27 tert-Butyl 2-{ [2-(3-Trifluoromethylbenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate yellow solid; m.p. 65-72oC. 5 Reference Example 28 Methyl 2-{ [2-(4-Biphenylcarbonyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate white solid. Anal for C31H28N206S: 10 Calc'd: C,66.9; H,5.1; N,5.0; Found: C,66.1; H,5.0; N,5.1. Reference Example 29 Methyl 2-{[2-(Cyclopropylcarbonyl)aminobenzyl]-(4 15 methoxybenzenesulfonyl)amino}acrylate yellow oil. Anal. for C22H24N206S: Calc'd: C,59.5; H,5.4; N,6.3; Found: C,60.0; H,5.7; N,6.0; Mass spectrum (ES) 445.5 (M+H). 20 Reference Example 30 Methyl 2-{ [2-(Cyclohexylcarbonyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate white foam. Anal. for C25H30N206S: 25 Calc'd: C,61.7; H,6.2; N,5.8; Found: C,59.1; H,6.0; N,5.4; Mass spectrum (ES) 487.5 (M+H). Reference Example 31 30 Methyl 2-{ [2-(3-Fluorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 32 Methyl 2-{ [2-(3-Chlorobenzoyl)aminobenzyl]-(4 35 methoxybenzenesulfonyl)amino}acrylate WO 99/37625 PCT/US99/01325 - 45 Reference Example 33 Methyl 2-{ [2-(2,4-Dichlorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate 5 Reference Example 34 Methyl 2-{ [2-(2,3-Difluorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 35 10 Methyl 2-{[2-(2-Chloro-4-fluorobenzoyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino }acrylate Reference Example 36 Methyl 2-{ [2-(2-Furanylcarbonyl)aminobenzyl]-(4 15 methoxybenzenesulfonyl)amino}acrylate off-white solid. Anal. for C23H22N207S. Calc'd: C,58.7; H,4.7; N,6.0; Found: C,58.0; H,4.1; N,3.8; Mass Spectrum (ES) 470.9 (M+H). 20 Reference Example 37 Methyl 2-((4-Methoxybenzenesulfonyl)-{2-[(3 thienylcarbonyl)amino]benzyl}amino)acrylate 25 Reference Example 38 Methyl 2-{ [2-(2-Acetylaminoacetyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 39 30 Methyl 2-{ [2-(2-Dimethylacetyl)aminobenzyl]-(4 methoxybenzenesulfonyl)amino}acrylate Reference Example 40 Methyl 2-{ [2-(Cyclobutylcarbonyl)aminobenzyl]-(4 35 methoxybenzenesulfonyl)amino}acrylate WO 99/37625 PCTIUS99/01325 - 46 Reference Example 41 Methyl 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a mixture of 0.449g (1 mmol) of methyl 2-[[2-(2-methoxyacetamido) 5 benzyl]-(4-methoxybenzene-sulfonyl]amino]acrylate in 5 mil of anhydrous methanol was added 0.109 g (1.3 mmol) of anhydrous sodium bicar-bonate. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. To the residue was added ethyl acetate and water. The organic layer was separated and washed with H20 and brine and then dried with Na2SO4. The solvent was removed to 10 give 0.41 g of solid. The solid was crystallized from ethyl acetate to give 0.28 g of white crystals, m.p. 160-163 0 C. Anal. for C21H24N207S: Calc'd: C,56.2; H,5.4; N,6.3; Found: C,56.1; H,5.3; N,6.3; S,6.9; Mass spectrum (ES) 449.1 (M+H). 15 Utilizing the procedure in Reference Example 41, the following intermediate compounds can be prepared from the appropriate methyl 2- { (4-methoxybenzene sulfonyl)-[2-(substituted amino)benzyl] amino) acrylates. 20 Reference Example 42 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl) 2,3,4,5-tetrahydro-1 H-[1,4]benzodiazepine-3-carboxylate white foam. Anal. for C25H26N207S2: Calc'd: C,56.6; H,4.9; N,5.3 25 Found: C,56.2; H,5.2; N,5.2. Reference Example 43 Methyl 1,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylate 30 white solid. Anal. for C25H26N208S2: Calc'd: C,54.9; H,4.8; N,5.1; Found: C,54.8; H,4.9; N,5.1.

WO 99/37625 PCT/US99/01325 -47 Reference Example 44 Methyl 1-Methanesulfonyl-4-(4-methoxybenzeuesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate white crystals, m.p. 136-137oC. Anal. for C19H22N207S2: 5 Calc'd: C.50.2; H,4.9; N,6.2; Found: C,50.1; H,4.9; N,6.4. Reference Example 45 Methyl 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 10 1H-[1,4]benzodiazepine-3-carboxylate tan solid. Anal. for C25H24N202S: Calc'd: C,62.2; H,5.4; N,5.8; Found: C,62.3; H,5.2; N,5.6. 15 Reference Example 46 Methyl 1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylate white crystals, m.p. 150-155oC. Anal. for C20H22N206S: Calc'd: C,57.4; H,5.3; N,6.7; 20 Found: C,56.6; H,5.2; N,6.5. Reference Example 47 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-2,3,4,5 tetrahydro-l1H-[ 1,4]benzodiazepine-3-carboxylate 25 off-white solid; Anal. for C24H23N306S: Calc'd: C,59.9; H,4.8; N,8.7; Found: C,59.2; H,4.8; N,8.3; Mass spectrum (ES) 482.2 (M+H). 30 Reference Example 48 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylate off-white solid. Anal. for C23H22N206S2: Calc'd: C,56.8; H,4.6; N,5.8; 35 Found: C,56.0; H,4.6; N,5.2.

WO 99/37625 PCT/US99/01325 -48 Reference Example 49 Methyl 4-(4-Methoxybenzenesulfonyl)- 1-(4-pyridinylcarbonyl)-2,3,4,5 tetrahydro- 1H- [1,4]benzodiazepine-3-carboxylate off-white crystals, m.p. 162-164oC. Anal. for C24H23N306S: 5 Calc'd: C.59.9; H,4.8; N,8.7; Found: C,59.9; H,4.8; N,8.7. Reference Example 50 Methyl 1-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 10 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate white solid; Anal. for C31H28N206S: Calc'd: C,66.9; H,5.1; N,5.0; Found: C,65.8; H,5.2; N,5.0; Mass spectrum (ES) 557.6 (M+H). 15 Reference Example 51 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(propane- 1-sulfonyl)-2,3,4,5 tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylate yellow oil. Anal. for C21H26N207S2: 20 Calc'd: C,52.3; H,5.4; N,5.8; Found: C,51.8: H,5.4; N,5.6. Reference Example 52 Methyl 1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl) 25 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate white foam. Anal. for C31H28N206S: Calc'd: C,66.9; H,5.1; N,5.0; Found: C,67.3; H,5.2; N,4.7; Mass spectrum (ES) 557.6 (M+H). 30 Reference Example 53 Methyl 1-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate WO 99/37625 PCT/US99/01325 - 49 Reference Example 54 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate white solid; Anal. for C26H25FN206S: 5 Calc'd: C,60.9; H,4.9; N,5.5; Found: C,60.9; H,5.0; N,5.0. Reference Example 55 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-fluorobenzoyl) 10 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 56 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5 tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylate 15 white solid; Anal. for C27H28N206S: Calc'd: C,63.8; H,5.6; N,5.5; Found: C,64.0; H,5.7; N,5.3: S,6.5. Reference Example 57 20 Methyl 4-(4-Methoxybenzenesulfonyl)- 1-(2-trifluoromethylbenzoyl) 2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 58 Methyl 1-(2-Chloro-6-trifluoromethylbenzoyl)-4(4 25 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3 carboxylate Reference Example 59 Methyl 1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4 30 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3 carboxylate Reference Example 60 Methyl 1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4 35 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3 carboxylate WO 99/37625 PCT/US99/01325 - 50 Reference Example 61 Methyl 4-(4-Methoxybenzenesulfonyl)-1l-(2-methylbenzoyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate 5 Reference Example 62 Methyl 4-(4-Methoxybenzenesulfonyl)-1l-(2-methyl-6-chlorobenzoyl) 2,3,4,5-tetrahydro- 1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 63 10 Methyl 1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 64 Methyl 1-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 15 2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 65 Methyl 1-(2-Chloro-4-fluorobenzoyi)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 20 Reference Example 66 Methyl 1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 25 Reference Example 67 Methyl 1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 68 30 Methyl 1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 69 Methyl 1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 35 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate WO 99/37625 PCT/US99/01325 -51 Reference Example 70 Methyl 1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Prepared according to the procedure set forth in Reference Example 10; white 5 solid. Anal. for C25H22C12N206S: Calc'd: C.54.7; H,4.0; N,5.1; Found: C,54.4; H,3.8: N,4.9: Mass spectrum (548.9) (M+H); 550.9 (M+H). 10 Reference Example 71 Methyl 1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-lH-[I1,4]benzodiazepine-3-carboxylate Reference Example 72 15 Methyl 1-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 73 Methyl 1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 20 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 74 Methyl 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro- 1 H-[ 1,4] benzodiazepine-3-carboxylate 25 Reference Example 75 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methylthiobenzoyl)-2,3,4,5 tetrahydro-1H-[I,4]benzodiazepine-3-carboxylate 30 Reference Example 76 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-thienylcarbonyl) 2,3,4,5-tetrahydro- 1H-[ 1.4]benzodiazepine-3-carboxylate Reference Example 77 35 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl) 2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate WO 99/37625 PCT/US99/01325 - 52 Reference Example 78 Methyl 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 5 Reference Example 79 Methyl 1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate off-white solid, m.p. 165-167 0 C. Anal. for C23H22N207S: Calc'd: C,58.7; H,4.7; N,6.0; 10 Found: C,58.4: H,4.6; N,5.7; Mass spectrum (ES) 470.9 (M+H). Reference Example 80 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl) 15 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 81 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methyl-2-furanylcarbonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 20 Reference Example 82 Methyl 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 25 Reference Example 83 Methyl 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 84 30 Methyl 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 85 Methyl 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 35 1H-[1,4]benzodiazepine-3-carboxylate WO 99/37625 PCT/US99/01325 - 53 Reference Example 86 Methyl 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 5 Reference Example 87 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5 tetrahydro- 1H-[1,4] benzodiazepine-3-carboxylate Reference Example 88 10 Methyl 1-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 89 Methyl 1 -(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 90 Methyl 1-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate 20 Reference Example 91 Methyl 1-(Chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Following the method described for Reference Example 18, 3.0 g (7.61 mmol) 25 of methyl 2-[2-aminobenzyl)-(4-methoxy-benzenesulfonyl)-amino]-3-hydroxy propionate was reacted with 1.82 ml (22.8 mmol) of chloroacetylchloride to give 4.0 g of solid. Chromatography on silica gel with ethyl acetate-hexane (1:1) as a solvent gave 1.5 g of methyl 2-[(2-chloroacetylaminobenzyl)-(4-methoxybenzenesulfonyl)-amino] acrylate. A 1.3 g sample of the preceding compound was reacted with 0.312 g of 30 anhydrous NaHCO3 in 10 ml of anhydrous methanol at room temperature overnight and the mixture was then heated at 80 0 C for 5 hours. The solvent was removed and the residue partitioned between H20 and ethyl acetate. The ethyl acetate extract was washed with brine, dried with Na2SO4 and the solvent removed. The residue was triturated with hexane-ethyl acetate, chilled and filtered to give the product; Mass 35 spectrum (ES) 453.1 (M+H).

WO 99/37625 PCT/US99/01325 - 54 Reference Example 92 Methyl 1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 5 Reference Example 93 Methyl 1-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylate Reference Example 94 10 Methyl 1-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro- 1H- [ 1,4]benzodiazepine-3-carboxylate white crystals, m.p. 98-100C. Anal. for C22H24N206S: Calc'd: C,59.5; H,5.4; N,6.3; Found: C,59.3; H,5.6; N,6.2; 15 Mass spectrum (ES) 445.1 (M+H). Reference Example 95 Methyl 1-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H- [1,4]benzodiazepine-3-carboxylate 20 Reference Example 96 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(trifluoroacetyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate To a solution of 1.0 g (2.54 mmol) of methyl 3-hydroxy-2-({(4 25 methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]amino }propionate in 10 ml of CH2Cl2 was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride. After 1 hour at room temperature, the solvent was removed. Dichloromethane was added several times and the solvent removed under vacuum after each addition. Methanol was then added 2 times and the solvent removed under vacuum to give methyl 2- { (4 30 methoxybenzenesulfonyl)-[2-(2,2,2-trifluoroacetylamino)benzyl]-amino} acrylate as a glass. The glass was dissolved in methanol and 0.213 g of anhydrous NaHCO3 was added. The mixture was stirred at room temperature overnight and concentrated under vacuum to dryness. To the residue was added ethyl acetate and water. The organic layer was separated, washed with H20, brine and dried with Na2SO4. The solvent 35 was removed and the residue (1.0 g) was chromatographed on silica gel thick layer WO 99/37625 PCT/US99/01325 - 55 plates with hexane-ethyl acetate (1:1) as solvent to give 0.365 g of product as a glass. Anal. for C20H 19F3N206S: Calc'd: C,50.9; H,4.1: N,5.9; F,12.1; S,6.7; Found: C,50.8; H,4.4; N,5.5; F,11.7; S,6.7; 5 Mass spectrum (ES) 473.1 (M+H). Reference Example 97 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 10 To 0.50 g (1.26 mmol) of 2-[(2-aminobenzyl)-(4-methoxybenzene sulfonyl)amino]-3-hydroxypropionate in 5 ml of pyridine cooled to 0OC was added 0.284 g (2.59 mmol) of tosyl chloride. The mixture was stirred at 0 0 C for 2 hours and then concentrated to remove the solvent. To the residue was added 8 ml of anhydrous ethanol and the mixture refluxed for 2 days. The mixture was concentrated to dryness 15 and ethyl acetate added. The mixture was washed with H20, 2 N citric acid, brine and dried with Na2SO4. The filtrate was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness to give 0.60 g of a foam. Anal. for C25H26N207S2: Calc'd: C,56.6; H,4.9; N,5.3; S,12.1; 20 Found: C,56.2; H,5.2; N,5.2; S,11.4; Mass spectrum (ES) 531.6 (M+H). Reference Example 98 Methyl 2-[(4-Methoxybenzenesulfonyl)-(2 25 methylsulfonylaminobenzyl)amino]acrylate To a solution of 1.0 g (2.54 mmol) of methyl [(2-aminobenzyl)-(4 methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of pyridine cooled to -5oC was added 0.432 ml (5.58 mmol) of methanesulfonyl chloride. The mixture was stirred at 0OC for 48 hours. To the mixture was added ice and H20 and the mixture was 30 extracted with ethyl acetate. The extract was washed with H20, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue triturated with ethyl acetate-hexane to give 0.90 g of a solid, 128-142oC. Anal. for C 19H22N207S2: Calc'd: C,50.2; H,4.9; N,6.2; S,14.1; 35 Found: C,49.6; H,5.0; N,6.9; S,14.0; Mass spectrum (ES) 455.5 (M+H).

WO 99/37625 PCT/US99/01325 -56 Reference Example 99 Methyl 1,4-Bis-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylate To a solution of 1.0 g (2.34 mmol) of methyl 2-[(2-aminobenzyl)-(4 5 methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 6 ml of pyridine cooled to 0 0 C to -5oC was added 1.07 (5.18 mmol) of 4-methoxybenzenesulfonyl chloride. After 2 hours, the mixture was concentrated to dryness under vacuum. To the residue was added 12 ml of ethanol and the mixture refluxed overnight. The solvent was removed under vacuum and the residue chromatographed on silica gel thick layer plates with 10 ethyl acetate-hexane (l:1) as solvent to give 0.83 g (60%) of product as a white foam; Anal. calc'd for C25H26N208S2: C,54.9; H,4.8; N,5.1; S,11.7. Found: C,54.8; H,4.9; N,5.0; S,11.5; Mass spectrum (ES) 547.1 (M+H); and a second component (0.38 g) methyl 2- { [2-(4-methoxybenzenesulfonyl)amninobenzyl]-(4-methoxybenzene sulfonyl)amino}-3-hydroxypropionate. Anal. for C25H28N209S2: 15 Calc'd: C,53.2; H,5.0; N,5.0; S,11.4; Found: C,51.8; H,5.1; N,4.7; S,11.3; Mass spectrum (ES) 565.2 (M+H). Reference Example 100 20 Methyl 1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylate To a solution of 0.70 g (1.52 mmol) of methyl 2-[(2-diacetylaminobenzyl)-(4 methoxybenzenesulfonyl) amino]acrylate in 5 ml of anhydrous methanol was added 0.332 g (3.95 mmol) of anhydrous sodium bicarbonate. The mixture was stirred at 25 room temperature overnight and the solvent removed under vacuum. To the residue was added ethyl acetate and H20. The organic layer was separated, washed with brine and dried with Na2SO4. The solvent was removed and the residue dried under vacuum to give 0.59 g of white crystals, m.p. 150-155 0 C. Anal. for C20H22N206S: Calc'd: C,57.4; H,5.3; N,6.7; S,7.7; 30 Found: C,56.6; H,5.2; N,6.5; S,7.5; Mass spectrum (ES) 419.9 (M+H). Reference Example 101 Methyl 3-Acetoxy-2-[(2-diacetylaminobenzyl)-(4 35 methoxybenzenesulfonyl)amino]propionate A mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4 methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 1.3 ml of acetic anhydride WO 99/37625 PCT/US99/01325 - 57 in 8 ml of toluene was heated at 100 0 C for 2 hours. The mixture was concentrated and 3 ml of acetic anhydride added thereto. The mixture was heated at 100oC overnight and concentrated to dryness under high vacuum to give an oil. The oil was dried at 75 0 C under vacuum for 48 hours to give 1.2 g of a yellow oil. Anal. for C24H28N209S: 5 Calc'd: C,54.5; H,5.2; N,5.5; S,6.2; Found: C,54.6; H,5.1; N,5.4; S,6.4; Mass spectrum (ES) 520.8 (M+H). Reference Example 102 10 Methyl 2-[(2-Diacetylaminobenzyl)-(4 methoxybenzenesulfonyl)amino]acrylate A mixture of 1.0 g (1.97 mmol) of methyl 3-acetoxy-2-[(2-diacetyl aminobenzyl)-(4-methoxybenzenesulfonyl)amino]propionate and 0.826 ml (5.92 mmol) of triethylamine in 5 ml of CH2Cl2 was stirred at room temperature overnight. 15 The solution was diluted with 30 ml of CH2Cl2 and washed with 20 ml each of H20, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give a brown oil. Anal. for C22H24N207S: Calc'd: C,57.4; H,5.3; N,6.1; S,7.0; Found: C,56.2; H,5.5; N,5.6; S,7.2. 20 Reference Example 103 Methyl 2-{(4-Methoxybenzenesulfonyl)-[2-(2,2,2 trifluoroacetylamino)benzyl]amino}acrylate To a suspension of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4 25 methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of toluene was added 1.8 ml (12.7 mmol) of trifluoroacetic anhydride (solid dissolves). The solution was stirred for 2 hours at room temperature and heated at 100 0 C overnight. The mixture was then concentrated to dryness under vacuum. To the residue was added 0.9 ml of trifluoroacetic anhydride and the solution stirred at room temperature for 1.5 hours and 30 concentrated to dryness. To the residue was added 10 ml of toluene and the mixture refluxed for 2 hours. The solution was cooled to room temperature and 2.5 ml of triethylamine added and the mixture stirred at room temperature overnight. The solution was concentrated to dryness and the residue dissolved in ethyl acetate. The ethyl acetate was washed with H20, brine and dried (Na2SO4). The solvent was removed under 35 vacuum to give 1.0 g of colorless oil. Crystallization from ethyl acetate - hexane WO 99/37625 PCT/US99/01325 - 58 gave 0.625 g of colorless crystals, m.p. 120-121oC. Anal. for C20H19F3N206S: Calc'd: C,50.9; H,4.1; N,5.9; S,6.7; F,12.1; Found: C,50.8; H,4.2; N,5.6; S,6.8; F,11.9; 5 Mass spectrum (ES) 473.1 (M+H). Reference Example 104 4-(4-Methoxybenzenesulfonyl)-1 -(2-methyl-5-fluorobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic Acid 10 To a mixture of 1.9 g (3.71 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1 (2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro-IH-[1 ,4]benzodiazepine-3-carboxylate in 10 ml of tetrahydrofuran was added 5 ml (4.82 mmol) of I N NaOH. The mixture was stirred at room temperature for 1.5 hours and the solvent removed under vacuum. To the residue was added ethyl acetate and the mixture neutralized with I N HC1. The 15 organic layer was separated, washed with brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.41 g of white solid. Anal. for C25H23FN206S: Calc'd: C,60.2; H,4.7; N,5.6; Found: C,60.2; H,4.8; N,5.4 S,6.4; F,3.6; Mass spectrum (ES) 497.5 (M-H). 20 Utilizing the method described in Reference Example 104, the following benzodiazepine-3-carboxylic acids can be prepared. Reference Example 105 25 4-(4-Methoxybenzenesulfonyl)-1-(4-methylphenylsulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white foam. Anal. for C24H24N207S2: Calc'd: C,55.8; H,4.7; N,5.4; Found: C,53.9; H,5.1; N,4.8; 30 Mass spectrum (ES) 512.2 (M+H).

WO 99/37625 PCT/US99/01325 - 59 Reference Example 106 1,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid off-white solid. Anal. for C24H24N208S2: 5 Calc'd: C,54.1; H,4.5; N,5.3; Found: C,52.4: H,4.8; N,4.7; Mass spectrum (ES) 533.1 (M+H). Reference Example 107 10 1-Methanesulfonyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid white solid. Anal. for C 18H20N207S2: Calc'd: C,49.1; H,4.6; N,6.3; Found: C,47.5; H,5.0; N,5.5; 15 Mass spectrum (ES) 441.1 (M+H). Reference Example 108 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid 20 white foam. Anal. for C24H22N206S: Calc'd C,61.5; H,5.2; N,6.0; Found: C,60.8; H,5.2; N,5.7; Mass spectrum (ES) 467.9 (M+H). 25 Reference Example 109 1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H [1,4]benzodiazepine-3-carboxylic acid white solid; Anal. for Cl9H22N206S: Calc'd: C,56.4; H,5.0; N,6.9; 30 Found: C,55.2; H,4.9; N,6.6; S,7.8; Mass spectrum (ES) 404.9 (M+H).

WO 99/37625 PCT/US99/01325 - 60 Reference Example 110 4-(4-Methoxybenzenesulfonyl)- 1 -(3-pyridinylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white solid; m.p. 250-255. Anal. for C23H21N306S: 5 Calc'd: C,59.1; H,4.5; N,9.0; Found: C,58.3; H,4.7; N,8.3; Mass spectrum (ES); 468.2 (M+H). Reference Example 111 10 4-(4-Methoxybenzenesulfonyl)-1 -(2-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white solid; Anal. for C22H20N206S2: Calc'd: C,55.9; H,4.3; N,5.9; Found: C,54.9; H,4.4; N,5.4; 15 Mass spectrum (ES) 473.1 (M+H). Reference Example 112 1 -Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H [1,4]benzodiazepine-3-carboxylic acid 20 white crystals, m.p. 193-194 0 C. Anal. for C20H22N207S: Calc'd: C,55.3: H,5.1; N,6.5; Found: C,55.1; H,4.9; N,6.2; Mass spectrum (ES) 433.1 (M-H). 25 Reference Example 113 4-(4-Methoxybenzenesulfonyl)- I -(4-pyridinylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white crystals, m.p. 258-261oC. Anal. for C23H21N306S: Calc'd: C,59.1; H,4.5; N,9.0; 30 Found: C,58.8; H,4.5; N,8.8; Mass spectrum (ES) 483.3 (M+H).

WO 99/37625 PCT/US99/01325 -61 Reference Example 114 1-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[ 1,4]benzodiazepine-3-carboxylic acid white foam. Anal. for C30H26N206S: 5 Calc'd: C,66.4; H.4.8; N,5.2; Found: C,64.7; H,5.2; N,4.8; Mass spectrum (ES) 543.6 (M+H). Reference Example 115 10 4-(4-Methoxybenzenesulfonyl)- 1 -(propane-I -sulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white foam. Anal. for C20H24N207S2: Calc'd: C,51.3; H,5.2; N,6.0; Found: C,50.3; H,5.3; N,5.7; 15 Mass spectrum (ES) 467.3 (M-H). Reference Example 116 1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 20 white foam; m.p. 106-145 0 C. Anal. for C30H26N206S: Calc'd: C,66.4; H,4.8; N,5.2; Found: C,65.7; H,5.0; N,4.8; Mass spectrum (ES) 541.1 (M-H). 25 Reference Example 117 1-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 118 30 4-(4-Methoxybenzenesulfonyl)- 1 -(2-methyl-3-fluorobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid WO 99/37625 PCT/US99/01325 - 62 Reference Example 119 4-(4-Methoxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white solid. Anal. for C26H26N206S: 5 Calc'd: C,63.1; H.5.3; N,5.7; Found: C,61.5: H,5.4; N,5.2; Mass spectrum (ES) 493.2 (M-H). Reference Example 120 10 4-(4-Methoxybenzenesulfonyl)-1-(2-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 121 1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 15 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 122 1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 20 Reference Example 123 1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 25 Reference Example 124 4-(4-Methoxybenzenesulfonyl)- 1-(2-methylbenzoyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 125 30 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 126 1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 35 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid WO 99/37625 PCT/US99/01325 - 63 Reference Example 127 1-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 5 Reference Example 128 1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 129 10 1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 130 1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 15 1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 131 1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 20 Reference Example 132 1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 25 Reference Example 133 1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white solid. Anal. for C24H20Cl2N206S: Calc'd: C,53.8; H,3.8; N,5.2; 30 Found: C,52.8; H,3.9; N,4.9; Mass spectrum (ES) 533 (M-H). Reference Example 134 1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 35 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid WO 99/37625 PCT/US99/01325 - 64 Reference Example 135 1-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 5 Reference Example 136 1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 137 10 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 138 4-(4-Methoxybenzenesulfonyl)-1-(2-methylthiobenzoyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 139 4-(4-Methoxybenzenesulfonyl)-1l-(3-methyl-2-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 20 Reference Example 140 4-(4-Methoxybenzenesulfonyl)-1l-(4-methyl-2-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 25 Reference Example 141 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 142 30 1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white solid. Anal. for C22H20N207S: Calc'd: C, 57.9; H, 4.4; N, 6.1; Found: C, 56.5; H, 4.5; N, 5.7; 35 Mass spectrum (ES) 455.1 (M-H).

WO 99/37625 PCT/US99/01325 - 65 Reference Example 143 4-(4-Methoxybenzenesulfonyl)-1-(3-methyl-2-furanylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 5 Reference Example 144 4-(4-Methoxybenzenesulfonyl)-1l-(4-methyl-2-furanylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 145 10 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 146 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 147 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid 20 Reference Example 148 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid 25 Reference Example 149 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 150 30 4-(4-Methoxybenzenesulfonyl)-1-(3-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 151 4-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 35 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid WO 99/37625 PCT/US99/01325 - 66 Reference Example 152 1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid 5 Reference Example 153 1-(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid Reference Example 154 10 1-(Pyrrolidinoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 155 1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 156 1 -(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid 20 white crystals, m.p. 131-135oC. Anal. for C21H22N206S: Calc'd: C,58.6; H,5.2; N,6.5; Found: C,58.1; H,5.5; N,5.8; Mass spectrum (ES) 431.5 (M+H). 25 Reference Example 157 1-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid Reference Example 158 30 1-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid white solid. Anal. for C24H28N206S: Calc'd: C,61.0; H,6.0; N,5.9; Found: C,57.0; H,5.7; N,5.4; 35 Mass spectrum (ES) 471.5 (M-H).

WO 99/37625 PCT/US99/01325 - 67 Reference Example 159 (D,L)N-(4-Methoxybenzenesulfonyl)-O-(2-tetrahydropyranyl)serine, Methyl ester A mixture of 1.44 g (5 mmol) of N-(4-methoxybenzenesulfonyl)serine, methyl 5 ester; 1.05 g (12.5 mmol) of 3,4-dihydro-2H-pyran and 9.5 mg of 4-methyl benzenesulfonic acid monohydrate in 5 ml of tetrahydrofuran was refluxed overnight and the mixture was concentrated to dryness under vaccum. The residue was extracted with CH2Cl2 and the extract washed with 2 N NaHCO3, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate 10 and the filter pad washed with CH2Cl2. The filtrate was concentrated to dryness and the residue (2.3 g) was extracted with three 50 ml portions of hot hexane to give 1.92 g of product as a yellow oil; Mass spectrum (ES) 374.4 (MH+). Reference Example 160 15 Methyl 3-Hydroxy-2-{ [4-methoxybenzenesulfonyl]-[2-(4 morpholinocarbonylamino)benzyl]amino}propionate To a mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl)-(4 methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 8 ml of pyridine chilled at 0'( to -10'C was added 740 pL (6.34 mmol) of morpholinocarbonyl chloride. The mixture 20 was kept at 0' to 5 0 C overnight. The mixture was concentrated under vacuum and diluted with ethyl acetate. The solution was washed with H20, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.61 g of solid (yellow-orange foam). The solid was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:3) as solvent to give 0.86 g of solid. Anal. for 25 C23H29N308S: Calc'd: C,54.4; H,5.8; N,8.3; Found: C,53.9; H,5.7; N,8.1; Mass spectrum (ES) 508.4 (M+H). 30 Reference Example 161 Methyl 2-{ (4-Methoxybenzenesulfonyl)- [2-(4 morpholinocarbonylamino)benzyl]amino}acrylate To a solution of 0.70 g (1.38 mmol) of methyl 3-hydroxy-2- { [4-methoxy benzenesulfonyl ]-[2-(4-morpholinocarbonylamino)benzyl]amino }propionate and 769 35 pL (5.54 mmol) of triethylamine in 8 ml of CH2C12, cooled to 0OC, was added 0.386 g (2.03 mmol) of 4-methylbenzenesulfonyl chloride. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with CH2Cl2. The extract WO 99/37625 PCT/US99/01325 - 68 was washed with 2 N citric acid, brine and dried with Na2SO4. The solvent was removed to give 0.67 g of a yellow oil. Anal. for C23H27N307S: Calc'd: C,56.4; H,5.6; N,8.6; S,6.6; Found: C,56.1; H,5.8; N,8.3; S,6.6. 5 Reference Example 162 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-morpholinocarbonyl) 2,3,4,5-tetrahydro-1 H-[ 1,4]-benzodiazepine-3-carboxylate A mixture of 0.50 g (1.02 mmol) of methyl 2-{ (4-methoxybenzenesulfonyl)-[2 10 (4-morpholinocarbonyl-amino)benzyl]amino}acrylate and 0.111 g (1.32 mmol) of anhydrous NaHCO3 in 5 ml of anhydrous methanol was stirred at room temperature for 16 hours. An additional 55 mg of NaHCO3 was added and the mixture stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue diluted with H20 and extracted with ethyl acetate. The extract was washed with brine 15 and dried with Na2SO4. The solvent was removed and the residue triturated with hexane-ethyl acetate to give 0.36 g of a yellow solid; Anal. calc'd for C23H27N307S: C,56.4; H,5.6; N,8.6; S,6.6. Found: C,56.5; H,5.7; N,8.4; S,6.7; Mass spectrum (ES) 490.3 (M+H). 20 Reference Example 163 4-(4-Methoxybenzenesulfonyl)- 1 -(4-morpholinocarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic Acid A mixture of 0.36 g (0.735 mmol) of methyl 4-(4-methoxybenzenesulfonyl)- I (4-morpholinocarbonyl)-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylate and 25 1 ml (0.95 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the acidified with 1 N HCI and cooled. The mixture was filtered and the solid washed with water to give 0.26 g of white solid. Anal. for C22H25N307S: Calc'd: C,55.6; H,5.3; N,8.8; 30 Found: C,53.5; H,5.6; N,8.3; Mass spectrum (ES) 474.3 (M-H).

WO 99/37625 PCT/US99/01325 - 69 Reference Example 164 Methyl 3-[(2-Tetrahydropyranyl)oxy]-2-[(4-methoxybenzenesulfonyl) (2-nitro-4-chlorobenzyl)amino]propionate To a mixture of 1.67 g (4.4 mmol) of (D,L) N-(4-methoxybenzenesulfonyl)-O 5 (2-tetrahydropyranyl) serine, methyl ester, 0.825 g (4.4 mol) of 4-chloro-2-nitrobenzyl alcohol and 1.16 g (4.4 mmol) of triphenylphosphine in 4.5 ml of tetrahydrofuran was added dropwise a solution of 0.766 g (4.4 mmol) of diethyl azodicarboxylate in 1 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether, filtered and the 10 filtrate passed through a thin pad of hydrous magnesium silicate. The pad was washed with ethyl acetate and the total filtrate concentrated to dryness under vacuum to give 4.54 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (55:45) as solvent. The fractions containing product were combined and the solvent removed to give 0.55 g of oily solid; Mass spectrum (ES) 543.1 (M+H). 15 Reference Example 165 Methyl 2-{ [2-(4-Pyridinylmethyleneamino)benzyl]-[4 methoxybenzenesulfonyl]amino}-3-hydroxypropionate A mixture of 0.50 g (1.268 mmol) of methyl 2-[(2-aminobenzyl)-(4 20 methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 1.268 mmol of 4 pyridinecarboxaldehyde in 7 ml of anhydrous ethanol was refluxed for 1.5 hours and the mixture concentrated under vacuum to dryness. To the residue was added H20 and ethyl acetate. The ethyl acetate layer was separated and concentrated to dryness under vacuum. The solid was purified by thick layer chromatography on silica gel with 25 hexane-ethyl acetate as solvent to give 0.40 g of solid product (plus a small amount of starting material). Anal. for C24H25N306S: Calc'd: C,59.6; H,5.2; N,8.7; Found: C,57.6; H,5.7; N,7.4; Mass spectrum (ES) 484 (M+H)-product; 395.1 (M+H)-starting material. 30 Reference Example 166 Methyl 1-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H- [1,4]benzodiazepine-3-carboxylate To a solution of 0.80 g (1.64 mmol) of methyl 2- { [2-(cyclohexylcarbonyl) 35 aminobenzyl]-(4-methoxybenzenesulfonyl)amino}acrylate in 10 ml of methanol was added 0.207 g (2.46 mmol) of anhydrous sodium bicarbonate. The mixture was stirred for 2 days and then an additional 0.207 g of NaHCO3 added. The mixture was stirred WO 99/37625 PCT/US99/01325 - 70 overnight and the solvent removed under vacuum. To the residue was added H20 and ethyl acetate and the organic layer separated. The ethyl acetate extract was washed with brine, dried with Na2SO4 and the solvent removed under vacuum to give 0.83 g of the product as a yellow oil. Anal. for C25H30N206S: Calc'd: C,61.7; H,6.2; N,5.8; 5 Found: C,61.0; H,6.4; N,5.3; Mass spectrum (ES) 487.0 (M+H). Reference Example 167 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2 10 nitrobenzyl)amino]propionate To a solution of 0.289 g (1 mmol) of methyl 3-hydroxy-2-(4 methoxybenzenesulfonylamino)propionate in 4 ml of N,N-dimethylformamide cooled in an ice bath was added 40 mg of NaH (60% in oil) (1 mmol). After the gas evolution ceased, 0.165 g (1.1 mmol) of sodium iodide was added, followed by the addition of 15 0.226 g (1.1 nunol) of 4-chloro-2-nitrobenzyl chloride in 1 ml of dimethylformamide. The solution became purple and was stirred at room temperature over the weekend. The solvent was removed under vacuum and the residue extracted with CH2Cl2. The extract was washed with H20, brine and dried with Na2SO4. The solvent was removed to give 0.53 g of solid which was chromatographed on thick layer silica gel 20 plates with hexane-ethyl acetate (2:1) as solvent to give 0.143 g (31 %) of product, as crystals, m.p. 1120-114oC. Anal. for C18H19CIN208S: Calc'd: C,47.2; H,4.2; N,6.1; Found: C,47.0; H,4.1; N,6.0; Mass spectrum (ES) 459.2 (M+H). 25 Reference Example 168 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2 aminobenzyl)amino]propionate A mixture of 0.454 g (1 mmol) of methyl 3-hydroxy-2-[(4-methoxy 30 benzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate and 0.451 g (2 mmol) of SnC12*2H20 in 12 ml of methanol was refluxed for 2 hours. An additional 0.451 g (2 mmol) of SnCI2*2H20 was added and the mixture refluxed for 2 hours. The solvent was removed and ethyl acetate added. The mixture was neutralized with 1 N NaHCO3 and then stirred for 1 hour and filtered. The ethyl acetate layer was separated and 35 washed with H20, brine and dried with Na2SO4. The solvent was removed to give 0.42 g of solid which was chromatographed on thick layer silica gel plates with hexane- WO 99/37625 PCT/US99/01325 -71 ethyl acetate (45:55) as solvent to give 60 mg of product (RF 0.66) as a glass, m.p. 99'-1 12C. Anal. for C18H21CIN206S: Calc'd: C,50.4; H,4.9: N,6.5; Found: C,49.7; H,4.9; N,6.4; 5 Mass spectrum (ES) 429.1 (M+H). Reference Example 169 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(4-chloro-2 aminobenzyl)amino]propionate 10 To a solution of 0.458 g (1 mmol) of methyl 3-hydroxy-2-[(4 methoxybenzenesulfonyl)-(4-chloro-2-nitrobenzyl)amino]propionate in 25 ml of ethanol and 25 ml of ethyl acetate was added 0.045 g of 10% Pd/C (wet - 50% H20). The mixture was shaken in a Parr hydrogenator under 35 pounds per square inch of hydrogen for 3 hours. The mixture was filtered through diatomaceous earth and the 15 filtrate was concentrated to dryness under vacuum to give 0.47 g of the product as a solid (approximately 90% pure). Thin layer chromatography on silica gel, NMR and Mass spectrum (ES) 429.1 (M+H) 395.1 (M+H) indicated approximately 10% of deschloro derivative. 20 A mixture of 4.74 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(4 chloro-2-aminobenzyl)amino} propionate, and 0.470 g of 10% Pd/C (wet-50% H20) in 200 ml of ethyl acetate-ethanol (1:1) was shaken in a Parr hydrogenator under 35 psi of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the solvent removed to give 4.5 g of solid. The solid was chromatographed by HPLC on a 25 Waters Prep machine with a 4 x 30 cm silica gel column with a step gradient of hexane ethyl acetate (9:1 to 6:4 to 1:1 to 0:100) to give 1.56 g of a glass, m.p. 110o-123oC. Anal. for C18H21 CIN206S: Calc'd: C, 50.4; H, 4.9; N, 6.5; Cl, 8.3; Found: C, 50.3; H, 4.8; N, 6.5; Cl, 7.8. 30 Reference Example 170 N-(4-Methoxybenzenesulfonyl)-glycine, Methyl Ester To a mixture of 12.5 g (0.1 mol) of glycine, methyl ester hydrochloride in 120 ml of CH2CI2, cooled in an ice bath was added 41.7 ml (0.3 mol) of triethylamine, 35 followed by the dropwise addition of a solution of 20.65 g (0.1 mol) of 4 methoxybenzenesulfonyl chloride in 40 ml of CH2CI2. The mixture was stirred at room temperature overnight and poured into water. The organic layer was separated WO 99/37625 PCT/US99/01325 - 72 and washed with 2 N citric acid, H20, 1 N NaHCO3. brine and dried with Na2SO4. The solvent was removed under vacuum to give 24.6 g of residue which was triturated with ethyl acetate to give 19.9 g of crystals, m.p. 59 0 -61 0 C. Anal. for C10HI3NSO5: Calc'd: C,46.3; H,5.1; N,5.4; 5 Found: C,46.2: H.5.0; N,5.2. Reference Example 171 Methyl 2

-[(

4 -methoxybenzenesulfonyl)-(2-nitrobenzyl)amino]acetate To a stirred and cooled mixture of 1.2 g (30 mmol) of NaH (58% in oil) in 50 10 ml of N,N-dimethylformamide was added dropwise a solution of 7.78 g (30 mmol) of N-(4-methoxybenzenesulfonyl)glycine, methyl ester in 40 ml of N,N-dimethyl formamide. After gas evolution ceased, a solution of 6.80 g (32 mmol) of 2 nitrobenzyl bromide in 40 ml of N,N-dimethylformamnide was added dropwise to the mixture. The mixture was then stirred at room temperature overnight under nitrogen 15 and the solvent removed under vacuum. The residue was extracted with CH2Cl2 and the extract washed with H20, 2 N citric acid, H20, I N NaHCO3, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2Cl2. The filtrate was concentrated under vacuum to give 11.79 g of solid. Trituration with ethyl acetate gave 2.64 g (22%) of crystals, 20 m.p. 114oC-116oC. Anal. for C17H18N207S: Calc'd: C,51.8; H,4.6; N,7.1; Found: C,51.7; H,4.6; N,7.1. From the mother liquors an additional 6.49 g (55%) of product as crystals was 25 obtained by chilling at 0oC and filtering the mother liquors. Reference Example 172 Methyl 2

-[(

2 -Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetate (A) To a mixture of 2.15 g (5.45 mmol) of methyl-2-[(4-methoxy 30 benzenesulfonyl)-(2-nitrobenzyl)amnino]acetate and 1.57 g (25 mmol) of ammonium formate in 10 ml of anhydrous methanol was added 0.42 g of 10% palladium on carbon. The mixture was stirred at room temperature for 1.5 hours and then filtered through diatomaceous earth. The filtrate was concentrated to dryness under vacuum and the residue diluted with H20 (25 ml) and extracted with CH2Cl 2 (75 ml). The 35 extract was washed with brine, dried with Na2SO4 and the solvent removed to give 0.45 g of solid. Crystallization from ethyl acetate gave 0.124 g of white crystals, m.p. 100 0 -102 0 C. Anal. for C17H20N20 5

S:

WO 99/37625 PCT/US99/01325 - 73 Calc'd: C,56.0: H,5.5; N,7.7; Found: C,56.1; H,5.6; N,7.6. (B) To a solution of 4.2 g of methyl 2-[(4-methoxybenzenesulfonyl)-(2 5 nitrobenzyl)amino]acetate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.42 g of 10% Pd on carbon (wet -50% H20) and the mixture shaken in a Parr hydrogenator under 35 pounds per square inch of hydrogen for 4.5 hours at room temperature. The mixture was filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 4.0 g of crystals, m.p. 100o-102'C. 10 Reference Example 173 2

-[(

2 -Aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetic Acid To a solution of 5.14 g (14.1 mmol) of methyl 2-[(2-aminobenzyl)-(4 methoxybenzenesulfonyl)amino] acetate in 50 ml of methanol-tetrahydrofuran (1: 1) was 15 added 2.86 ml of 10 N NaOH and the mixture refluxed for 2 hours. The solvent was removed under vacuum and the residue partitioned between water and ether. The water layer was separated and acidified with 2 N citric acid. The solid was filtered, washed with H20 and dried in a vacuum oven at room temperature to give 4.45 g (91%) of crystals, m.p. 145 0 -147oC. Anal. for CI6H18N205S: 20 Calc'd: C,54.9; H,5.2; N,8.0; Found: C,55.1; H,5.2; N,7.9. Reference Example 174 Methyl 4-(4-Methoxybenzenesulfonyl)- 1 -(phenoxyacetyl)-2,3,4,5 25 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0OC) mixture of 1.5 g (3.8 mmol) of methyl 2 -[(2-aminobenzyl)

(

4 -methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.7 ml (19 mmol) of triethylamine in 15 ml of CH2Cl2 was added 1.58 g (11.4 mol) of phenoxyacetyl chloride. The mixture was stirred at room temperature overnight and filtered. The 30 filtrate was washed with H20, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed to give 2.4 g of crude methyl 2- { ( 4 -methoxybenzenesulfonyl)-[2 (phenoxyacetylamino)benzyl]amino}acrylate as an oil. Anal. for C26H26N207S: Calc'd: C,61.2: H,5.1; N,5.5; Found: C,62.6; H,5.1; N,4.0; 35 Mass spectrum (ES) 511 (M+H).

WO 99/37625 PCT/US99/01325 - 74 To a 2.0 g (3.92 mrnmol) sample of the preceding compound in 15 ml of methanol was added 0.494 g of anhydrous NaHCO3 and the mixture stirred for 5 hours. The mixture was concentrated under vacuum and ethyl acetate and H20 were added to the residue. The mixture was filtered and the organic layer of the filtrate 5 separated, washed with brine and dried with Na2SO4. The solvent was removed to give 0.36 g of product as off-white crystals, m.p. 151o-153oC. Anal. for C26H26N207S: Calc'd: C,61.2; H,5.1; N,5.5; Found: C,61.1; H,5.1; N,5.4; 10 Mass spectrum (ES) 511 (M+H). Reference Example 175 3-hydroxymethyl-4-(4-Methoxybenzenesulfonyl)-l (3-pyridinylmethyl)-2,3,4,5-tetrahydro- 1H- [ 1,4]benzodiazepine 15 A mixture of 0.100 g (0.208 mmol) of methyl 4-(4-methoxybenzenesulfonyl) 1 -(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro- I H-[ 1,4]benzodiazepine-3-carboxylate and 3 ml of borane-tetrahydroforan complex in tetrahydrofuran (1.0 M) was refluxed overnight. The solution was cooled to room temperature, diluted with methanol and the solvent removed. Methanol was added several times and, after each addition, the 20 solvent was removed. To the residue was added 1IN NaHCO3. The mixture was stirred for 45 minutes and then extracted with ethyl acetate. The extract was concentrated and then washed with H20, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue chromatographed on thick layer silica gel plates with 10% methanol in ethyl acetate as solvent to give 60 mg of solid (RF 0.26). 25 Crystallization from ethyl acetate gave 30 mg of white crystals. Anal. for C23H25N304S: Calc'd: C,62.8; H,5.7; N,9.6; S,7.3; Found: C,61.1; H,5.6; N,9.2; S,7.3; Mass spectrum (ES) 440.2 (M+H). 30 Reference Example 176 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxypyridinyl-3 carbonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0 0 C) mixture of 1.0 g (2.54 mmol) of methyl 2-[(2-aminobenzyl) 35 (4-methoxybenzenesulfonyl) amino]-3-hydroxypropionate and 1.8 ml (12.68 mmol) of triethylamine in 10 ml of CH2Cl2 was added 0.957 g (5.58 mmol) of 2 methoxypyridine-3-carbonyl chloride in 4 ml of CH2CI2. The solution was stirred at WO 99/37625 PCT/US99/01325 - 75 room temperature overnight, diluted with H20 and CH2Cl2 and the organic layer separated. The organic layer was washed with H20, 2 N citric acid, and brine and dried with Na2SO4. The solvent was removed under vacuum to give 1.2 g of solid. The solid was chromatographed on thick layer silica gel plates with ethyl acetate-hexane 5 (3:1) as solvent to give 0.27 g of yellow foam. Anal. for C25H25N307S: Calc'd: C,58.7, H,4.93: N,8.21: Found: C,57.8; H,4.5; N,8.3: S,6.2. Reference Example 177 10 5-Methyl-2-nitrobenzyl Bromide To a cooled (ice-water bath) mixture of 30% HBr in acetic acid (3 ml) was added 2.5 g 5-methyl-2-nitrobenzyl alcohol and the chilled solution stirred for 2 hours. The mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with H20, brine and the solvent removed under vacuum to give a mixture 15 of product (50%) and starting material (50%). Reference Example 178 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(5-methyl-2 nitrobenzyl)amino]propionate 20 A solution of 23.14 g (0.08 mol) of methyl 3-hydroxy-2-(4 methoxybenzenesulfonylamino)propionate in 120 ml of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 3.2 g (0.08 mol) of sodium hydride (57% in oil) in 120 ml of N,N-dimethylformide. When gas evolution ceased, the mixture was chilled in an ice bath and a solution of 16.4 g (0.084 mol) of 5-methyl-2 25 nitrobenzyl chloride in 100 ml of N,N-dimethylformamide was added. To the mixture was added 12.6 g (0.084 mol) of anhydrous sodium iodide and the mixture was chilled in an ice bath and stirred for 20 minutes. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under vacuum and the residue diluted with 200 ml of H20 and extracted with 500 ml of ethyl acetate. The 30 aqueous layer was extracted with an additional 200 ml of ethyl acetate. The combined extract was washed with H20, brine and dried with Na2SO4. The solvent was removed to give 41.18 g of crude product. The product was chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 8.14 g (RF 0.38) of product as a yellow semi-solid. From a small scale run (1 mmol) the product was chromatographed 35 twice on thick silica gel plates with hexane-ethyl acetate (1:1) to give 0.12 g of a yellow semi-solid. Anal. for C 19H22N2SO8: WO 99/37625 PCT/US99/01325 - 76 Calc'd: C,52.0: H,5.1; N,6.4; Found: C,51.7; H,5. l; N,6.0. Reference Example 179 5 Methyl 3-Hydroxy-2-[(4-methoxybenzenesulfonyl)-(2-amino-5 methylbenzyl)amino]propionate To a solution of 3.4 g of methyl 3-hydroxy-2-[(4-methoxybenzenesulfonyl)-(5 methyl-2-nitrobenzyl)-amino]propionate in 200 ml of ethanol-ethyl acetate (1:1) was added 0.34 g of 10% palladium on carbon (wet - 50% H20). The mixture was then 10 shaken in a Parr hydrogenator under 35 psi of hydrogen for 2.5 hours. The mixture was filtered through diatomaceous earth and the filtrate concentrated under vacuum to give 2.86 g of a brown oil. Anal. for C19H24N206S: Calc'd: C,55.9; H,5.9; N,6.9; Found: C,55.6; H,5.9; N,6.4; 15 Mass spectrum (ES) 409 (M+H). Reference Example 180 Methyl 3-[(2-Tetrahydropyranyl)oxy]-2-[(-4-methoxybenzenesulfonyl) (5-methyl-2-nitrobenzyl)amino]propionate 20 To a mixture of 1.75 g (4.68 mmol) of (D,L)N-(4-methoxybenzenesulfonyl)-O (2-tetrahydropyranyl) serine, methyl ester, 0.790 g (4.68 mmol) of 5-methyl-2 nitrobenzyl alcohol and 1.23 g (4.68 mmol) of triphenylphosphine in 4.5 ml of anhydrous tetrahydrofuran was added dropwise (over 15 minutes) a solution of 0.815 g (4.68 mmol) of diethyl azodicarboxylate (DEAD) in 1 ml of tetrahydrofuran. The 25 mixture was stirred at room temperature overnight and the solvent removed under vacuum. The residue was triturated with diethyl ether and the solid filtered off. The filtrate was concentrated to dryness under vacuum to give 4.67 g of solid. The solid was chromatographed on silica gel with hexane-ethyl acetate (1:1) to give 0.56 g of product (RF 0.48). 30 Reference Example 181 Methyl 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl) 7-methyl-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0oC) mixture of 1.598 g (3.91 mmol) of methyl 3-hydroxy-2-(4 35 methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amino]propionate and 1.97 g (19.5) mmol) of triethylamine in 15 ml of dichloromethane was added 0.787 ml (8.60 mmol) of methoxyacetylchloride. The mixture was stirred at room temperature WO 99/37625 PCT/US99/01325 - 77 overnight. The mixture was then diluted with CH2CI2 and washed with H20. 2 N citric acid, H20. brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give 1.94 g of crude methyl 2- { [2-(methoxyacetylamino)-5-methylbenzyl]-(4-methoxy-benzene 5 sulfonyl)-amino } acrylate as a brown oil. Mass spectrum (ES) 463.4 (M+H). To a solution of 1.62 g (3.5 mmol) of the preceding compound in 15 ml of anhydrous methanol was added 0.382 g (4.50 mmol) of anhydrous NaHCO3 and the mixture was stirred overnight at room temperature. The solvent was removed under 10 vacuum and the residue partitioned between 100 ml of ethyl acetate and 20 ml of water. The ethyl acetate layer was separated and washed with H20, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give a yellow oil. Trituration with ethyl acetate-hexane gave 1.26 g (78%) of tan crystals, m. p. 122o-124oC. Anal. for 15 C22H26N207S: Calc'd: C,57.1; H,5.7; N,6.1; Found: C,57.4; H,5.7: N,6.0. Reference Example 182 20 Methyl 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazeprine-3-carboxylate To a cooled (0OC) mixture of 1.465 g (3.586 mmol) of methyl 3-hydroxy-2-[4 methoxybenzenesulfonyl)-(2-amino-5-methylbenzyl)amnino]propionate and 2.49 ml (17.93 mmol) of triethylamine in 20 ml of CH2CI2 was added 0.915 ml (7.89 mmol) 25 of benzoyl chloride. The mixture was stored at room temperature overnight, diluted with CH2CI2 and washed with H20, 2 N citric acid, H20, brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give 1.8 g of crude methyl 2-[(2 benzoylamino-5-methylbenzyl)-(4-methoxybenzenesulfonyl)amino]acrylate as a brown 30 oil. Anal. for C26H26N206S: Calc'd: C,63.1; H,5.3; N,5.7; Found: C,63.9; H,5.2; N,5.2. As described for Reference Example 181, 1.825 g (3.68 mmol) of the preceding 35 compound was stirred with 0.402 g (4.78 mmol) of NaHCO3 in 1.5 ml of methanol to give an oil. Trituration with hexane (plus several drops of ethyl acetate) gave crystals, m. p. 58 0 -62oC.

WO 99/37625 PCT/US99/01325 - 78 Reference Example 183 Methyl 1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl 2,3,4,5-tetrahydro- 1 H-[ 1,4]benzadiazepine-3-carboxylate 5 As described for Reference Examples 181 and 182. a mixture of 1.41 g (3.455 mmol) of methyl 3-hydroxy-2-[-(4-methoxybenzenesulfonyl)-(2-amino-5-methyl benzyl)amino]propionate, 1.75 g (17.3 mmol) of triethylamine and 0.809 ml of trans crotonyl chloride in 15 ml of CH2C12 was stirred overnight to give 1.52 g of methyl 2 { [2-(trans-crotonylamino)-5-methylbenzyl]-(4-methoxybenzenesulfonyl) 10 amino}acrylate as a brown oil; Mass spectrum (ES) 459.4 (M+H). As described in Reference Example 181, 1.52 g (3.31 mmol) of the preceding product was stirred with 0.362 g (4.3 mmol) of NaHCO3 in 15 ml of methanol at room temperature overnight. To the mixture was added 0.056 g of NaHCO3 and the mixture 15 was heated at 80 0 C for 3 hours and worked up as for Reference Example 181 to give a 1.05 g of a yellow glass, m. p. 75 0 -84oC. Mass spectrum (ES) 459.4 (M+H). Reference Example 184 1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5 20 tetrahydro-lH-[1,4]benzodiazepene-3-carboxylic acid A mixture of 1.26 g (2.72 mmol) of methyl 1-(trans-crotonyl)-4-(4 methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3 carboxylate and 3.53 ml (3.53 mmol) of 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The solvent was removed under vacuum and 25 the residue dissolved in H20 and the solution extracted with ethyl acetate. The aqueous layer was acidified with IN HCI (pH 2) and extracted with CH2C12. The CH2Cl2 extract was dried with Na2SO4 and the solvent removed to give 1.06 g (after drying under vacuum) of solid, m. p. 10l°-105o C. 30 Reference Example 185 1-(Benzoyl)-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3-4,5 tetrahydro-IH[1,4]benzodiazepine-3-carboxylic acid A mixture of 1.18g (2.38 mml) of methyl 1-(benzoyl)-4-(4-methoxy benzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- I H-[ 1, 4 ]benzodiazepine-3-carboxylate 35 and 3.09 ml (3.09 mmol) of IN NaOH in 10 ml of tetrahydrofuran was stored at room temperature overnight and the solvent removed under vacuum. The residue was diluted with H20, extracted with ethyl acetate and the aqueous layer acidified with 2N citric WO 99/37625 PCT/US99/01325 - 79 acid. The mixture was extracted with CH2Cl2 and the CH2Cl2 extracts were washed with H20, brine and dried with Na2SO4. The solvent was removed to give 0.82g of a light yellow glass, m.p. 95o-100oC; Mass spectrum (ES) 481.4 (M+H). 5 Reference Example 186 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5 tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylate A mixture of 1.6 g (3.57 mmol) of methyl 1-(methoxyacetyl)-4-(4 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylate 10 and 32 ml of borane in tetrahydrofuran (1.0 M) was refluxed under nitrogen overnight. Methanol was added and the solvent removed. To the residue was added 25 ml of CH2Cl2 and 25 ml of 2 N HCI and the mixture stirred at room temperature for 1 hour. The organic layer was separated and washed with H20 and concentrated to dryness. The residue was triturated with ethyl acetate-hexane, cooled and filtered to give 1.2 g of 15 white crystals, m.p. 86'-90oC; Mass spectrum (ES) 435.4 (M+H). Anal. for C21H26N206S: Calc'd: C,58.1; H,6.0; N,6.5; Found: C,58.5; H,6.0; N,6.5. 20 Reference Example 187 4-(4-Methoxybenzenesulfonyl)- 1-(2-methoxyethyl)-2,3,4,5-tetrahydro 1H[1,4]benzodiazepine-3-carboxylic acid A mixture of 1.0 g (2.3 mmol) of methyl 4-(4-methoxybenzenesulfonyl)-1-(2 methoxyethyl)-2,3,4,5-tetrahydro- 1 H- [ 1,4]benzodiazepine-3-carboxylate and 3.0 ml of 25 1 N NaOH in 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours and the solvent removed. To the residue was added water and the mixture acidified with 1 N HCI. The mixture was extracted with ethyl acetate and the extract was washed with brine and dried with Na2SO4. The solvent was removed and the residue triturated with ethyl acetate-hexane, cooled and filtered to give 0.65 g of white crystals, m.p. 1640 30 165oC; Mass spectrum (ES) 421.4 (M+H). Anal. for C20H24N206S: Calc'd: C,57.1; H,5.8; N,6.7; Found: C,57.3; H,5.7; N,6.4.

WO 99/37625 PCT/US99/01325 -80 Reference Example 188 Methyl 1-(Benzyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylate A mixture of 0.20 g (0.416 mmol) of methyl I-(benzoyl)-4-(4 5 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylate and 4 ml of borane in tetrahydrofuran (1.0 M) was refluxed overnight and the solvent removed. To the residue was added 5 ml of CH2Cl2 and 5 ml of 2N HCI and the mixture stirred for 1 hour. The organic layer was separated and concentrated to dryness. The residue was chromatographed on thick layer silica gel plates with hexane 10 ethyl acetate (2:1) as solvent to give 0.140 g of a colorless oil: Mass spectrum (ES) 467.5 (M+H). Reference Example 189 4-(4-Methoxybenzenesulfonyl)- 1 -[4-(trifluoromethoxy)benzoyl]-8 15 chloro-2,3,4,5-tetrahydro-1H[1,4]benzodiazepine-3-carboxylic acid As described for Reference Example 18, 1.46 g (3.40 mmol) of methyl 2-[(2 amino-4-chlorobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate was reacted with 4-(trifluoromethoxy)benzoyl chloride to give 2.59 g of methyl 2-{2-[4 (trifluoromethoxy) benzoyl]amino-4-chlorobenzyl]amino } acrylate as a yellow oil; Mass 20 spectrum (ES) 599.3 (M+H). The preceding compound was stirred with 0.445 g (5.29 mmol) of anhydrous NaHCO3 in 15 ml of methanol at room temperature for 16 hours and then was heated at 80'C for 2 hours. The solvent was removed and the residue extracted with ethyl acetate. The extract was washed with H20, brine, and dried (Na2SO4). The solvent was removed and the residue crystallized from ethyl acetate 25 hexane to give methyl 4-(4-methoxybenzenesulfonyl)- 1 -[4-(trifluoromethoxy)benzoyl I } 8-chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as yellow crystals, m.p. 149 0 -151oC. Anal. for C26H22C1F307S: Calc'd: C,52.1; H,3.7; N,4.7; C1,6.0; F,9.5; Found: C,51.8; H,3.6; N,4.7; C1,5.9; F,9.4. 30 1.58g (2.64 mmol) of the preceding compound was stirred with 3.43 ml of 1N NaOH in 10 ml of tetrahydrofuran at room temperature for 2 hours and worked up as for Reference Example 104 to give 1.52 g of product. Crystallization from ethyl acetate-hexane gave 1.2 g of white crystals, m.p. 184o - 186C. 35 WO 99/37625 PCT/US99/01325 -81 Reference Example 190 Methyl 4-(4-Methoxybenzenesulfonyl)-1-(4-morpholinoacetyl)-2,3,4,5 tetrahydro-1H[ 1,4]benzodiazepine-3-carboxylate A mixture of 0.10 g (0.22 rmmol) of methyl 1-(chloroacetyl)-4-(4 5 methoxybenzenesulfonyl)-2,3,4.5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate, 21.2 1 of morpholine and 125.4 tl of N,N-diisopropylethylamine in 3 ml of CH2Cl2 was stirred overnight at room temperature. An additional 2.2 tl of morpholine was added and the solution stirred for 2 days at room temperature. The mixture was diluted with CH2Cl2 and washed with H20, brine and dried with Na2SO4. The solvent was 10 removed to give the product as a solid, Mass spectrum (ES) 504.3 (M+H). Anal. for C24H29N307S: Calc'd: C,57.2; H,5.8: N,8.3; Found: C,56.5; H,5.6; N,8.1. 15 Reference Example 191 Methyl 4-(4-Methoxybenzenesulfonyl)-1-[2-(1 pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylate As described for the general reaction of ethyl 2-fluorobenzoate with amines set 20 forth in Tetrahedron, 53:7557-7576 (1997), ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N,N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for Cl 2

HI

12

N

2 0 2 : C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2:1) was 25 refluxed for 2 hrs and the solvent removed. The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 3.7g of product. The pH of the filtrate was adjusted to 4.5 and extracted with ethyl acetate. The extract was concentrated to dryness to give 1.5g of product. The two crops were combined to give 5.2g of 2-(1-pyrazolyl)benzoic acid, mp 140-142 0 C. To the preceding compound 30 (2.07 g) in 5 ml CH 2 C1 2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH 2 Cl 2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2 (1-pyrazolyl)benzoyl chloride as a yellow solid. 35 A 2.3 g sample of the preceding compound was reacted with 1.5g of the compound of Reference Example 179 in 15 ml of CH 2

CI

2 and 5.12 ml of triethylamine WO 99/37625 PCT/US99/01325 - 82 in the manner described for Reference Example 181 to give methyl 2-[(4 methoxybenzenesulfonyl)- { 2-[2-( 1-pyrazolyl)phenylcarbonyl]amino-5-methylbenzyl } amrnino]acrylate. This compound was cyclized with NaHCO 3 in methanol in the manner described in Reference Example 181 to give methyl 4 -(4-methoxybenzenesulfonyl)-1 5 [2-( 1 -pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine 3-carboxylate (m.p. 240-2420 C). A 1.16 g sample of the preceding compound was hydrolysed with 2.69 ml of IN NaOH in 10 ml of tetrahydrofuran in the manner described for Reference Example 10 104 to give 0.71 g of 4

-(

4 -methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenyl carbonyl)-7-methyl-2,3,4,5-tetrahydro- 1H[1,4]benzodiazepine-3- carboxylic acid (mp 149-151 0 C). Reference Example 192 15 Methyl 4-(4-Methoxybenzenesulfonyl)-1-[2-(4 morpholino)phenylcarbonyl}-8-chloro-2,3,4,5-tetrahydro-lH.

[1,4]benzodiazepine-3-carboxylate Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 53:7557, (1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 20 hrs to give 2-morpholinobenzoic acid, mp 156-157 0 C. A 1.8 g sample of this compound in 5 ml of CH 2 C1 2 (chilled) was added to a solution of 7.9 ml of oxalyl chloride in CH 2 Cl 2 (2M) followed by the addition of 0.058 ml of N,N dimethylformamide. The solution was stirred at room temperature for 6 hrs and the solvent removed. Toluene was added (2 times) and removed to give 2-(4 25 morpholino)benzoyl chloride as a yellow solid. The preceding 2-(4-morpholino)benzoyl chloride was reacted with methyl 2-[(2 amino- 4 -chlorobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in the manner described in Reference Examples 181 and 189, and the product was stirred with 30 NaHCO 3 in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-(4 morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3 carboxylate, as a white solid having a mp 100-105 0 C. To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 35 N NaOH and the solution was stirred at room temperature overnight. Acidification with 2N citric acid gave 0.82 g of 4-(4-methoxybenzenesulfonyl)-1-[2-(4-morpholino)- WO 99/37625 PCT/US99/01325 - 83 phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylic acid (mp 136-143 oC). Reference Example 193 5 Methyl 1-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[ 1, 4 ]benzodiazepine-3-carboxylate A mixture of 0.270 g of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4] benzodiazepine-3-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 pl of triethylamine in 5 ml of CH 2 Cl 2 was stirred 10 at room temperature overnight. The mixture was diluted with CHCl and HO20 and the

CH

2 Cl 2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.276g of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxy benzenesulfonyl)-2,3,4,5tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, (mp 187-190 0 C). 15 A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of IN NaOH in 4 ml of tetrahydrofuran. Dilution with HO 2 0 and acidification with 1IN HCI gave 0.40 g of the acid as a white solid, mp 144-152 0 C. 20 Reference Example 194 Methyl 4-(4-Methoxybenzenesulfonyl) -1-[2-chloro-4-(3-methyl-1 pyrazolyl)phenylcarbonyl}-2,3,4,5-tetrahydro -1H [1,4]benzodiazepine-3-carboxylate As described in Example 65, methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5 25 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate was reacted with 4-(3-methyl-1 pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-1 [2-chloro-4-(3-methyl- 1-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro- 1 H-[1,4]benzo diazepine-3-carboxylate as a white solid. Anal. for C 29

H

27 C1N 4 0 6 S: Calc'd: C, 58.3; H, 4.6; N, 9.4. 30 Found: C,58.2; H, 4.9; N, 8.9. This compound was hydrolysed with 1N NaOH in tetrahydrofuran as described in Reference Example 185 to give the benzodiazepine-3-carboxylic acid derivative as a white solid. 35 WO 99/37625 PCT/US99/01325 - 84 Reference Example 195 1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid A mixture of 1.7 g of the compound of Reference Example 45 and 25 ml of 5 borane in tetrahydrofuran (1.0 Molar) was refluxed under nitrogen overnight. To the solution was added 5 ml of CH 3 OH, CH2Cl2 (40 ml) and 30 ml of 2N HCI and the mixture stirred at room temperature for 1.5 hr. The organic layer was separated, washed with brine, dried with Na2SO4 and the solvent removed. The residue was crystallized from ethanol-hexane to give 1.15g of methyl 1-benzyl-4-(4 10 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122oC. A sample (1.0 g) of this compound was hydrolysed with 2.8 ml of 1 N NaOH in 7 ml of tetrahydrofuran as described in Reference Example 104 to give 0.64 g of the 2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid derivative as white crystals (mp 183-185 0 C). 15 Reference Example 196 Methyl 1-(2,4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a cooled (0OC) solution of 1.0 g (2.66 mmol) of 4-(4 20 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H- [ 1,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml (13.3 mmol) of triethylamine in 8 ml of

CH

2 Cl 2 was added 1.17 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH 2 Cl 2 and washed with 2 N citric acid. The organic layer was washed with H 2 0, 1 N Na 2

CO

3 , brine and 25 dried over Na 2

SO

4 . The solvent was removed and the residue was chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as an eluent to give 1.0 g of methyl 1-(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white foam. Anal. for

C

27

H

2 8

H

2 0 8 S: 30 Calc'd: C,60.0; H,5.2; N,5.2; Found: C,60.0; H,5.2; N,5.1; Mass Spectrum (ES): 541.0 (M+H). A 0.80 g (1.48 mmol) sample of the preceding compound and 1.92 ml (1.92 35 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HC1, chilled and filtered to give 0.70 g of 1-(2,4-dimethoxy- WO 99/37625 PCT/US99/01325 - 85 benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[ ,4]benzodiazepine 3-carboxylic acid as a white solid. Anal. for C 2 6

H

2 6

N

2 0 8 S: Calc'd: C,59.3; H,5.0; N,5.3; Found: C,56.1; H,4.8; N,5.0; 5 Mass Spectrum (ES): 527.0 (M+H). Reference Example 197 Methyl 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin- 1 yl)acetyl]-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 10 To a mixture of 2.5 g (6.64 mmol) of methyl 4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate (Reference Example 12) and 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH 2 Cl 2 cooled to 0°C was added to 1.65 g (14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0°C and 926 pl of triethylamine and 750 mg of 15 chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH 2 Cl 2 and H20. The insoluble solid was filtered off. The organic layer of the filtrate was separated, washed with brine, dried with Na 2

SO

4 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of 20 methyl 1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzo-diazepine-3-carboxylate (Reference Example 91). Anal. for

C

2 0

H

2 1 C1N 2 0 6 S: Calc'd: C,53.0; H,4.7; N,6.2; Found: C,51.6; H,4.6; N,5.7; 25 Mass Spectrum (ES): 453.0 (M+H). To a solution of 1.4 g (3.09 mmol) of the preceding compound in 12 ml of

CH

2 Cl 2 cooled to 0°C was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753.2 pl (6.79 mmol) of 1-methylpiperazine. The mixture 30 was stirred at room temperature overnight, diluted with CH 2 C1 2 , and washed with 2 N citric acid, H20, 1 M NaHCO 3 , brine and dried (Na 2

SO

4 ). The citric acid wash was made basic with saturated NaHCO 3 and then extracted with CH 2 Cl 2 . The extract was dried over Na 2

SO

4 and the solvent removed under vacuum to give 1.10 g of methyl 4 (4-methoxybenzenesulfonyl)-I-[2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5-tetrahydro 35 1H-[1,4]benzodiazepine-3-carboxylate as a white glass.

WO 99/37625 PCT/US99/01325 - 86 A mixture of 1.0 g (1.94 mmol) of the preceding compound and 2.3 ml (2.3 mmol) of 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours. The solvent was removed under vacuum. To the residue was added toluene (2 times) and the solvent removed under vacuum after each addition. The solid was dried at 65°C 5 under vacuum for 6 hours to give 1.1 g of potassium 4-(4-methoxybenzenesulfonyl)-1 [2-(4-methylpiperazin- 1 -yl)acetyl]-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3 carboxylate as a white solid. Reference Example 198 10 Methyl 1-Acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4] benzodiazepine-3-carboxylate To a cooled (00) solution of 2.0g (4.78 mmol) of methyl 1-acetyl-4-(4 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate in 14 ml of CH 2 C1 2 was added dropwise 143.3ml (14.3mmol) of a 1.0 molar solution of 15 BBr 3 in CH 2 C12. The mixture was stirred at room temperature for 1.5 hours. Ice and

H

2 0 were added to the reaction mixture and the insolubles filtered off. The filtrate was diluted with CH 2 C1 2 and H 2 0 and the CH 2

CI

2 layer separated, washed with brine and dried (Na 2

SO

4 ). The solvent was removed under vacuum to give 1.5 g of a white foam. The solid was chromatographed on silica gel with hexane-ethyl acetate (1:1) as 20 solvent to give a foam which was dried under vacuum to give 0.52 g of product as a white foam; Anal. Calc'd for Cl 9 H2oN 2 0 6 S: C, 56 4:H, 5.0; N, 6.9 Found: C 55.1; H, 4.7: N, 6.5. Reference Example 199 25 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2-thienylcarbonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate To a solution of 4.0 g (8.22 mmol) of methyl 4-(4 methoxybenzenesulfonyl)-l (2-thienylcarbonyl)-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylate in 17 ml of CH 2

CI

2 chilled to 0oC, was added slowly 16.4 ml (16.44 mmol) of 1.0 molar 30 solution of boron tribromide in CH 2 C1 2 . The mixture was stirred at room temperature overnight and diluted with CH 2 Cl 2 . The mixture was filtered and the solid washed with

CH

2

C

2 . and H 2 0. The filtrate was diluted with H 2 0 and the organic layer separated. The solvent was removed under vacuum and the solid chromatographed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 0.80 g of off white foam; Mass 35 Spectrum (ES) 473.5 (M+H); Anal. Calc'd for C 22

H

2 0

N

2 0 6

S

2 : C, 55.9; H, 4.3; N, 5.9. Found: C, 54.5; H, 4.4; N, 5.5.

WO 99/37625 PCT/US99/01325 - 87 Reference Example 200 Methyl 1-Benzoyl-4-(4-hydroxybenzenesulfonyl).-2,3,4,5. tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate To a solution of 9.8 g (20.39 mmol) of methyl 1-benzoyl-4-(4 5 methoxybenzenesulfonyl)-2,3,4,5-tetraydro-1H-[1,4]benzodiazepine in 50 mrnl of

CH

2 C2 cooled to 00, was added slowly 40.8 ml (40.8 mmol) of a 1.0 molar solution of BBr 3 in CH 2 Cl2. The mixture was stirred under nitrogen at room temperature overnight. Ice and H 2 0 were added and the mixture diluted with CH 2 Cl2. The organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined 10 organic extracts (CH 2 Cl 2 I+ethyl acetate) were concentrated under vacuum and the residue dissolved in ethyl acetate. The solution was washed with H20, brine and dried (Na 2

SO

4 ). The solution was filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue was chromatographed on silica gel with hexane-ethyl acetate as solvent to give 8 g of product as an off-white foam; Mass 15 Spectrum (ES) 467 (M+H); Anal Calc'd for C 2 4

H

2 2

N

2 0 6 S: C, 61.8; H, 4.8; N, 6.0. Found: C, 61.3; H, 4.6; N, 5.8. Utilizing the method described in Reference Examples 191-193, the following methyl- 1 -substituted-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H-[1,4] 20 benzodiazepine-3-carboxylates can be prepared. Reference Example 201 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-methylphenylsulfonyl) 2,3,4,5-tetrahydro-1H-[1, 4 ]benzodiazepine-3-carboxylate. 25 Reference Example 202 Methyl 1-Methanesulfonyl-4-(4-hydroxybenzenesulfonyl).-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepinef-3-carboxylate 6.0 g (13.2 mmol) of Reference Example 44 and 22.6 ml (22.6 mmol) of BBr 3 30 in CH 2 C2 (solution) gave, after chromatography on silica with ethyl acetate-hexane (1:1), 0.82g of a white foam; Mass spectrum (ES) 440.9 (M + H). Reference Example 203 Methyl 4 -(4-Hydroxybenzenesulfonyl)-l-(3-pyridinylcarbonyl) 2,3,4,5 35 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate WO 99/37625 PCT/US99/01325 - 88 Reference Example 204 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-pyridinylcarbonyl-2,3,4,5. tetrahydro- 1H- [1,4]benzodiazepine-3-carboxylate 5 Reference Example 205 Methyl 1-(4-Biphenylcarbonl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 206 10 Methyl 4-(4-Hydroxybenzenesulfonyl)- 1-(propane- 1-sulfonyl)-2,3,4,5 tetrahydro-l1H-[1, 4 ]benzodiazepine-3-carboxylate Reference Example 207 Methyl 1-([1,1'-Biphenyl]- 2 -carbonyl)-4-(4-hydroxybenzenesulfonyl).

15 2

,

3

,

4 ,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 208 Methyl 1-(3-Fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate 20 Reference Example 209 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2-methyl-5-fluorobenzoyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate 25 Reference Example 210 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-methyl-3-fluorobenzoyl) 2,3,4,5-tetrahydro-1H-[1, 4 ]benzodiazepine-3-carboxylate Reference Example 211 30 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(3-phenylpropionyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate WO 99/37625 PCT/US99/01325 - 89 Reference Example 212 Methyl 4-(4-Hydroxybenzenesulfonyl)-l1-(2-trifluoromethylbenzoyl) 2,3,4,5-tetrahydro-1H-[1, 4 ]benzodiazepine-3-carboxylate 5 Reference Example 213 Methyl 1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4 hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H-[1,4]benzodiazepine-3 carboxylate 10 Reference Example 214 Methyl 1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4 hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3 carboxylate 15 Reference Example 215 Methyl 1-(2-Fluoro-6-trifluoromethybenzoyl)-4-(4 hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH-[1,4]benzodiazepine-3 carboxylate 20 Reference Example 216 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2 methylbenzoyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 217 25 Methyl 4-(4-Hydroxybenzenesulfonyl)-l-(2-methyl-6-chlorobenzoyl) 2,3,4,5-tetrahydro-1H-[1, 4 ]benzodiazepine-3-carboxylateReference Example 218 Methyl 1-(2,4-Dimethylbenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 30 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 219 Methyl 1-(2,5-Dimethylbenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[ 1,4]benzodiazepine-3-carboxylate 35 WO 99/37625 PCT/US99/01325 - 90 Reference Example 220 Methyl 1-(2-Chloro-4-fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1, 4 ]benzodiazepine-3-carboxylate 5 Reference Example 221 Methyl 1-(2-Chlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylate Reference Example 222 10 Methyl 1-(2-Fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 223 Methyl 1-( 2 -Chloro- 6 -fluorobenzoyl)-4-(4-hydroxybenzenesulfonyl) 15 2

,

3

,

4 ,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 224 Methyl 1-(2,3-Difluorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[ 1,4]benzodiazepine-3-carboxylate 20 Reference Example 225 Methyl 1-(2,4-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylate 25 Reference Example 226 Methyl 1-(2,3-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl).-2,3,4,5-. tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 227 30 Methyl-1-(2,5-Dichlorobenzoyl)-4-(4-hydroxybenzenesulfonyl).-2,3,4,5.

tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 228 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(2-methylthiobenzoyl).-2,3,4,5 35 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylate WO 99/37625 PCT/US99/01325 -91 Reference Example 229 Methyl 4-(4-Hydroxybenzenesulfonyl)- 1-(3-methyl-2-thienylcarbonyl) 2,3,4,5-tetrahydro- 1H-[1, 4 ]benzodiazepine-3-carboxylate 5 Reference Example 230 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2-thienylcarbonyl) 2,3,4,5- tetrahydro-1H-[1, 4 ]benzodiazepine-3-carboxylate Reference Example 231 10 Methyl 1-(3-Chloro-2-thienylcarbonyl)-4-( hydroxybenzenesulfonyl) 2,3,4,5- tetrahydro-1H-[1, 4 ]benzodiazepine-3-carboxylate Reference Example 232 Methyl 1-( 2 -Furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate To a solution of 3.0g (6.38 mmol) of methyl 1-(2 furanylcarbonyl)-4-(4 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylate in., 15 ml of CH 2 C2 (cooled to 0OC ) was added dropwise 12.8ml (2.8 mmol) of BBr 3 in CH 2 C1 2 (1.0 M in CH 2

CI

2 ).The mixture was stirred at room temperature for 3 days, 20 diluted with CH 2 C1 2 and then ice was added. The organic layer was separated, washed with H 2 0, brine and dried (Na 2

SO

4 ). The solvent was removed and the residue chromatographed on silica gel (flash column) with ethyl acetate-hexane (1:1) as solvent. The fractions containing product were combined, the solvent removed and the residue triturated with ethyl acetate. Chilling and filtering gave 0.72g of methyl 1-(2- furanyl 25 carbonyl)-4-hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H-[ 1,4]benzodiazepine-3 carboxylate as a white solid, mp 204-206'C; Anal Cal'd for C 22

H

20

N

2 0 7 S: C, 57.9; H, 4.2; N, 6.1. Found: C,57.2; H,4.3; N, 6.0.;Mass spectrum (ES) 457.1 (M+H). Reference Example 233 30 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(3-methyl-2 furanylcarbonyl)-2,3,4,5- tetrahydro-1H-[-1,4]benzodiazepine-3. carboxylate WO 99/37625 PCT/US99/01325 - 92 Reference Example 234 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(4-methyl-2 furanylcarbonyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3 carboxylate 5 Reference Example 235 Methyl 1-(5-Chloro-2-furanylcarbonyl)-4-(4 hydroxybenzenesulfonyl)-2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine 3-carboxylate 10 Reference Example 236 Methyl 1-(5-Chloro-2-thienylcarbonyl)-4-(4 hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1,4]benzodeiazepine 3-carboxylate 15 Reference Example 237 Methyl 1- Propionyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodeiazepine-3-carboxylate 20 Reference Example 238 Methyl 1-Hexanoyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate Reference Example 239 25 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(3-thienylcarbonyl). 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 24 Methyl 1-(3-Furanylcarbonyl)-4-(4-hydroxybenzenesulfonyl). 30 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate Reference Example 241 Methyl 1-(Acetylaminoacetyl)-4-(4-hydroxybenzenesulfonyl). 2,3,4,5-tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylate 35 WO 99/37625 PCT/US99/01325 - 93 Reference Example 242 Methyl 1-(N,N Dimethylaminoacetyl)-4-(4 hydroxybenzenesulfonyl)- 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine 3-carboxylate 5 Reference Example 243 Methyl 1-(Cyclopropylcarbonyl)-4-(4-hydroxybenzenesulfonyl) 2,3,4,5-tetrahydro- 1H-[ 1,4]benzodiazepine To a solution of 4..44g(10 mmol) of methyl 1-cyclopropylcarbonyl-4-(4 10 methoxybenzenefulfonyl)-2,3,4-tetrahydro-1H-[1,4]benzodiaxepine -3-carboxylate in 25 ml of CH 2 C1 2 chilled to 0 C was added dropwise 22 ml (22 mmol) of BBr 3 in

CH

2 Cl 2 (1.0 molar solution). The mixture was stirred overnight, cooled and diluted with ice and H 2 0. Dichloromethane was added and the organic layer separated and washed with H20, brine and dried (Na 2

SO

4 ). The solvent was removed under vacuum 15 to give a solid which was chromatographed on silica gel with the solvent ethyl acetate hexane (1:1) to give 1.0 g of methyl 1-cyclopropylcarbonyl-4-(4-hydroxybenzene sulfonyl)-2,3,4,5-tetrahydro-lH-[1,4]benzodiazepine-3-carboxylate as a foam; Mass spectrum (ES) 431.3 (M+H). 20 Reference Example 244 Methyl 4-(4-Hydroxybenzenesulfonyl)-1-(trifluoroacetyl) -2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine Example 1 25 4-(4-Methoxybenzenesulfonyl)-1-(3-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide To a solution of 0.297 g (0.556 mmol) of 4-(4-methoxybenzenesulfonyl)-l-(3 trifluoromethylbenzoyl)-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylic acid from Reference Example 9 in 5 ml of CH2C2, was added 0.556 ml (1.11 mmol) of 30 2.0 M oxalyl chloride in CH2Cl2 and 0.044 ml of N,N-dimethylformamide. The mixture was stirred under nitrogen at room temperature for 1.5 hours and cooled in an ice bath. To this solution was added a chilled mixture of 0.156 g (2.24 mmol) of hydroxylamine hydrochloride and 4.68 ml (3.36 mmol) of triethylamine in 1.39 ml of tetrahydrofuran and 0.33 ml of H20. The mixture was stirred at room temperature 35 overnight and diluted with CH2CI2. The mixture was washed with 2 N citric acid, H20, 1 N NaHCO3, brine and dried with Na2SO4. The solvent was removed under vacuum to give 0.29 g of solid. Chromatography on thick layer silica gel plates with WO 99/37625 PCT/US99/01325 - 94 ethyl acetate-methanol (9:1) gave 60 mg of solid, m.p. 128-130'C. Anal. for C25H22F3N306S: Calc'd: C,54.6; H,4.0; N,7.7; Found: C,54.1: H,4.2; N,7.3. 5 Utilizing the procedure described in Example 1, the following compounds are prepared from the appropriately 1-substituted-4(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[ 1,4]benzodiazepine-3-carboxylic acids. 10 Example 2 4-(4-Methoxybenzenesulfonyl)- 1-(4-methylphenylsulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C24H25N307S2: Calc'd: C,54.2; H,4.7; N,7.9; 15 Found: C,53.5; H,5.2; N,7.3. Example 3 1 -Methanesulfonyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro. 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 20 Solid. Anal. for C 18H21N307S2: Calc'd: C,47.5; H,4.7; N,9.2; Found: C,46.8; H,4.8; N,8.5. Example 4 25 1,4-Bis-(4-Methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C24H25N308S2: Calc'd: C,52.6; H,4.6; N,7.7; Found: C,52.2; H,4.8; N,7.3. 30 Example 5 1 -Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1

H

[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White solid. Anal. for C24H23N306S: 35 Calc'd: C,59.9; H,4.8; N,8.7.; Found: C,59.2; H,4.6; N,8.6; S, 6.4; Mass spectrum (ES) 482.3 (M+H).

WO 99/37625 PCTIUS99/01325 - 95 Example 6 1-Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 5 White crystals. m.p. 195-197oC. Anal. for C19H21N306S: Calc'd: C,54.4; H,5.1; N,10.0; Found: C,52.6; H,4.9; N,9.4. Example 7 10 4-(4-Methoxybenzenesulfonyl)- 1 -(3-pyridinylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals, mrn.p. 167-169oC. Anal. for C23H22N406S: Calc'd: C,57.3: H,4.6; N,11.6; Found: 55.3; H,4.6; N,10.6. 15 Example 8 4-(4-Methoxybenzenesulfonyl)-- -(2-t hienylcarbonyl)-2,3,4,5 tetrahydro-IH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White solid. Anal. for C22H21N306S2: 20 Calc'd: C,54.2; H,4.3; N,8.6; Found: C,53.7; H,4.4; N,8.1. Example 9 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1 H 25 [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals, m.p. 143-145oC. Anal. for C20H23N307S: Calc'd: C,53.4; H,5.2; N,9.4; Found: C,53.9; H,5.6; N,8.5. 30 Example 10 4-(4-Methoxybenzenesulfonyl)-1 -(propane-1 -sulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Off-white solid. Anal. for C20H25N307S2: Calc'd: C,49.7; H,5.2; N,8.7; 35 Found: C,48.9; H,5.3; N,8.4.

WO 99/37625 PCT/US99/01325 - 96 Example 11 4-(4-Methoxybenzenesulfonyl)- 1 -(2-methyl-5-fluorobenzoyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Off-white solid. Anal. for C25H24FN306S: 5 Calc'd: C,58.5: H.4.7; N,8.2; Found: C,57.1; H,4.8; N,7.6. Example 12 4-(4-Methoxybenzenesulfonyl)- 1-(3-phenylpropionyl)-2,3,4,5 10 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Solid. Anal. for C26H27N306S: Calc'd: C,61.3; H,5.3; N,8.3; Found: C,59.8; H,5.3; N,7.5. 15 Example 13 4-(4-Methoxybenzenesulfonyl)- 1-( 4 -pyridinylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide White crystals, m.p. 155-165oC. Anal. for C23H22N406S: Calc'd: C,57.3; H,4.6; N,11.6; 20 Found: C,56.8: H,4.9; N,10.9. Example 14 1-([1,1'-Biphenyl]-2-carbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 25 Purified by chromatography on silica gel thick layer plates with hexane-ethyl acetate as solvent to give a white solid; m.p. 176-178oC. Anal. for C30H27N306S: Calc'd: C,64.6; H,4.9; N,7.5; Found: C,63.7; H,4.6; N,7.1.

WO 99/37625 PCT/US99/01325 - 97 Example 15 1-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Purified by chromatography on silica gel thick layer plates with hexane-ethyl 5 acetate (1:1) as solvent to give a white solid, m.p. 160-168 0 C. Anal. for C30H27N306S: Calc'd: C,64.6; H,4.9; N,7.5; Found: C,61.2; H,4.9; N,7.0; Mass spectrum (ES) 558.1 (M+H). 10 Example 16 1-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 15 Example 17 4-(4-Methoxybenzenesulfonyl)- 1 -(2-methyl-3-fluorobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 18 20 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-3-trifluoromethylbenzoyl) 2,3,4,5-tetrahydro- 1 H-[ 1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 19 25 1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 20 30 1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 21 35 1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro-1 H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide WO 99/37625 PCT/US99/01325 - 98 Example 22 4-(4-Methoxybenzenesulfonyl)- 1-(2-methylbenzoyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 5 Example 23 4-(4-Methoxybenzenesulfonyl)-1-(2-methyl-6-chlorobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 10 Example 24 1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 25 15 1-(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 26 1-(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 20 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 27 1-(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 25 Example 28 1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 30 Example 29 1-(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 30 35 1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide WO 99/37625 PCT/US99/01325 - 99 Example 31 1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide white crystals, m.p. 158-162oC. Anal. for C24H21C12N306S: 5 Calc'd: C,52.4: H.3.9; N,7.6; Found: C,52.1; H,3.8; N,7.5; Mass spectrum (ES) 549.9 (M+H); 552.0 (M+H). Example 32 10 1-(2,3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 33 1-(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 34 1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 20 Example 35 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesul Ifonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide 25 Example 36 4-(4-Methoxybenzenesulfonyl)-1-(2-methylthiobenzoyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 37 30 4-(4-Methoxybenzenesulfonyl)-1l-(3-methyl-2-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 38 4-(4-(Methoxybenzenesulfonyl)- 1 -(4-methyl-2-thienylcarbonyl)-2,3,4,5 35 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide WO 99/37625 PCT/US99/01325 - 100 Example 39 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 5 Example 40 1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide white solid. Anal. for C22H21N307S: Calc'd: C, 56.0; H, 4.5; N, 8.9; 10 Found: C, 55.6; H, 4.8; N, 8.3; Mass spectrum (ES) 472.0 (M+H). Example 41 4-(4-Methoxybenzenesulfonyl)- 1 -(3-methyl-2-furanylcarbonyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 42 4-(4-Methoxybenzenesulfonyl)- 1-(4-methyl-2-furanylcarbonyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 20 Example 43 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 25 Example 44 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 45 30 1-Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 46 1-Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H 35 [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide WO 99/37625 PCT/US99/01325 - 101 Example 47 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 5 Example 48 4-(4-Methoxybenzenesulfonyl)-1l-(3-thienylcarbonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 49 10 1-(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 50 1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 15 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 51 1 -(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 20 Example 52 1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 25 Example 53 1 -(Aminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 54 30 1-(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-l1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide WO 99/37625 PCT/US99/01325 - 102 Example 55 1 -(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide off-white solid. Anal. for C21H23N306S: 5 Calc'd: C,56.6: H,5.2; N,9.4; Found: C,55.1: H,5.2; N,8.8; Mass spectrum (ES) 446.5 (M+H). Example 56 10 1-(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 57 1-(Cyclohexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 15 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide off-white solid. Anal. for C24H29N306S: Calc'd: C,59.1; H,6.0; N,8.6; Found: C,58.0; H,6.0; N,8.1; Mass spectrum (ES) 488.6 (M+H). 20 Example 58 4-(4-Methoxybenzenesulfonyl)-1-(phenoxyacetyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxamide A mixture of 0.70 g (1.37mmol) of methyl 4-(4-methoxybenzenesulfonyl)-l 25 (phenoxyacetyl)-2,3,4-5-tetrahydro-lH[1,4]benzodiazepine-3-carboxylate and 1.8 ml (1.78 mmol) of IN NaOH in 3 ml of tetrahydrofuran was stirred at room temperature for 2 hours. The mixture was diluted with 3 ml of H20 and acidified with IN HCI to give a gummy solid. Ethyl acetate was added thereto and the mixture was chilled overnight. Filtration gave 4-(4-methoxybenzenesulfonyl)-1-(phenoxyacetyl)-2,3,4,5 30 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid as crystals, m.p. 188o-191oC. To a 0.496 g (1 mmol) sample of the preceeding compound in 5 ml of CH2Cl2 cooled to 0 0 C, was added 1 ml (2 mmol) of oxalyl chloride followed by the addition of 77.4 pl (1 mmol) of N,N-dimethylformamide. The mixture was stirred at room 35 temperature under nitrogen for 1 hour (referred to as solution A). In a separate flask was added 0.278 g (4 mmol) of hydroxyamine hydrochloride, 0.5 ml of H20 and 836.3 pIl (5 mmol) of triethylamine. The mixture was stirred for 20 minutes and then WO 99/37625 PCT/US99/01325 - 103 cooled to 0OC (referred to as solution B). The cooled solution B was added to the cooled (0OC) and stirred solution A and then this mixture was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated under vacuum, diluted with CH2CI2 and washed with H20, 2N citric acid, IN NaHCO3, and brine 5 and dried with Na2SO4. The solvent was removed and the residue crystallized from hexane-ethyl acetate (3:97) to give 0.396 g of white crystals, m.p. 159 0 -163oC. Anal. for C25H25N307S; Calc'd: C,58.7: H,4.9, N,8.2; Found: C,58.4; H,5.1; N,7.8; 10 Mass spectrum (ES) 512 (M+H). Example 59 1-Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3-4,5 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamine 15 A mixture of 1.26 g (2.72 mmol) of methyl 1-methoxyacetyl-4-(4 methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- I H-[1,4]benzodiazepine-3 carboxylate from Reference Example 181, 3.53 ml of IN NaOH and 10 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The solvent was then removed under vacuum and the residue dissolved in H 2 0 and extracted with ethyl 20 acetate. The aqueuous layer was acidified with IN HCI and then extracted with

CH

2

CI

2 . The CH 2 Cl 2 layer was dried over Na 2

SO

4 and the solvent removed to provide a solid. This material was dried in a vacuum oven and given 1.06 of solid, m.p. 101-105oC. 25 A 1.02 g (2.27 mmol) sample of 1-methoxyacetyl-4-(4-methoxy benzenesulfonyl)-7-methyl-2,3-4,5-tetrahydro- 1H-[1 ,4]benzodiazepine-3-carboxylic acid prepared above was dissolved in 2.57 ml of IN KOH. Toluene was added several times and the solvent was removed after each addition. The residue was dried in a vacuum oven to give 1.1 g of potassium salt. A mixture of 2.26 ml (4.52 mmol) of 30 oxalyl chloride in 20 ml of CH2Cl2 was cooled at 0OC and 0.351 ml (4.52 mmol) of N,N-dimethylformamide (DMF) was added dropwise. The mixture was stirred for 5 minutes and the potassium salt (1. I g) was added. The mixture was allowed to warm to room temperature and was stirred for 2 hours under nitrogen. The mixture was cooled (0OC) and this mixture was added to a cooled (0OC) mixture of 0.628 g (9.04 35 mmol) of hydroxylamine hydrochloride, 1.89 ml (13.56 mmol) of triethylamine in 1 ml of tetrahydrofuran-water (8:2). The mixture was stirred and chilled at 0 0 C for 10 minutes and then stirred at room temperature overnight. The solvent was removed WO 99/37625 PCT/US99/01325 - 104 under vacuum and the residue diluted with CH2Cl2-H20 and acidified with 2 N citric acid (pH 4). The CH2Cl2 layer was separated and washed with H20. IN NaHCO3. H20. and brine and dried with Na2SO4. The solution was filtered through a thin pad of hydrous magnesium silicate and the solvent removed under vacuum to give 0.73 g of 5 solid. Crystallization from ethyl acetate gave 0.32 g of crystals, m.p. 146 0 -148 0 C. Example 60 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro 1H[1,4]benzodianzepine-3-carboxylic acid, Hydroxyamide 10 In the manner described in Example 59, 0.83 g (1.71 mmol) of 1-benzoyl-4-(4 methoxybenzene-sulfonyl)-7-methyl-2,3,4,5-tetrahydro- I H[ 1,4]benzodianzepine-3 carboxylic acid from Reference Example 185 was converted to the potassium salt with 1.87 ml of IN KOH and the salt reacted with oxalyl chloride-DMF to give the acid chloride which was reacted with hydroxylamine. The solid from the reaction gave from 15 CH2Cl2 0.20 g. of yellow solid, m.p. 137o-139 0 C. Example 61 4-(4-Methoxybenzenesulfonyl)-1 -[4-(trifluoromethoxy)benzoyl]-8 chloro-2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, 20 Hydroxyamide In the manner described for Example 59, the potassium salt was prepared from 1.20 g of 4-(4-methoxybenzenesulfonyl)- 1-[4-(trifluoromethoxy)benzoyl)-8-chloro 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid from Reference Example 189, m.p. 184'-186oC and reacted with oxalyl chloride-DMF and the acid chloride 25 reacted with hydroxylamine to give 1.20 g of solid. Chromatography on thick layer silica gel plates with ethyl acetate-methanol (95:5) gave 0.58 g of solid m.p. 1340 dec; Mass spectrum (ES) 601 (M+H). Example 62 30 4-(4-Methoxybenzenesulfonyl)-1-(2-methoxyethyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide In the manner described for Example 1, 0.55 g of 4-(4-methoxy benzenesulfonyl)- 1 -(2-methoxyethyl)-2,3,4,5-tetrahydro- 1 H-[1,4]-benzodiazepine-3 carboxylic acid from Reference Example 187 was reacted with oxalyl chloride and the 35 resulting acid chloride reacted with hydroxylamine to 0.40 g of solid. Chromatography on thick layer silica gel plates with ethyl acetate-methanol (7:3) gave 0.150 g of product WO 99/37625 PCT/US99/01325 - 105 as an off-white foam; Mass spectrum (ES) 434.3 (M-H) Anal. for C20H25N306S: Calc'd: C,55.2; H,5.8; N,9.7; Found: C,54.0; H,5.8; N,9.3. 5 Example 63 4-(4-Methoxybenzenesulfonyl)-1-[2- (1 pyrazolyl)phenylcarbonyl]2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3 carboxylic acid, Hydroxyamide. 10 As described for the general reaction of ethyl 2-fluorobenzoate with amines set forth in Tetrahedron, 53, 7557-7576 (1997), ethyl 2-fluorobenzoate was reacted with pyrazole by refluxing N, N-dimethylformamide to give ethyl 2-(1-pyrazolyl)benzoate, as a thick yellow oil. Anal. Calc'd: for C 1 2

H

12

N

2 0 2 : C, 66.7; H, 5.6; N 13.0: Found: C, 66.5: H, 5.4: N, 12.9; Mass spectrum (ES) 217.2 (M+H). A sample (7.02g) of this 15 compound and 8.42 ml of 5N NaOH in 40 ml of ethanol-tetrahydrofuran (2:1) was refluxed for 2 hrs and the solvent removed.The residue was made acidic (pH6) with 2N citric acid and the precipated solid was filtered to obtain 3.7g of product. The pH of the filtrate was adjusted to 4.5 and extracted with ethyl acetate. The extract was concentrated to dryness to give 1.5g of product. The two crops were combined to give 20 5.2g of 2-(1-pyrazolyl)benzoic acid, mp 140-142 0 C. To the preceding compound (2.07 g) in 5 ml CH 2 C1 2 (chilled in an ice bath )was added 11.1 ml of a 2 Molar solution of oxalyl chloride in CH2C1 2 and 0.085 ml of N,N-dimethylformamide. The mixture was allowed to warm to room temperature and stirred for 4 hours. The solvent was removed and 25 ml of toluene added (twice) and removed under vacuum to give 2 25 (1-pyrazolyl)benzoyl chloride as a yellow solid. A 2.3 g sample of the preceding compound was reacted with 1.5g of the compound of Reference Example 179 in 15 ml of CH 2 Cl 2 and 5.12 ml of triethylamine in the manner described for Reference Example 181 to give methyl 2-[ (4 30 methoxybenzenesulfonyl)- { 2-[2-(1-pyrazolyl)phenylcarbonyl]amino-5-methylbenzyl } amino]acrylate. This compound was cyclized with NaHCO 3 in methanol in the manner described in Reference Example 181 to give methyl 4-(4-methoxybenzenesulfonyl)-1 [2-( 1 -pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine 3-carboxylate, m.p. 240-2420 C. 35 A 1.16 g sample of the preceding compound was hydrolysed with 2.69 ml of 1N NaOH in 10 ml of tetrahydrofuran in the manner described for Reference Example WO 99/37625 PCT/US99/01325 - 106 104 to give 0.71 g of 4-(4-methoxybenzenesulfonyl)-1-[2-(1-pyrazolyl)phenyl carbonyl)-7-methyl-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3- carboxylic acid, mp 149-151 0 C. 5 In the manner described in Example 59, 1.1 g of the preceding compound was converted to the potassium salt and reacted with oxalyl chloride and then hydroxylamine to give the above-identified product as white crystals, mp 194-196oC. Example 64 10 4-(4-Methoxybenzenesulfonyl)- 1 -[2-(4 morpholino)phenylcarbonyl}-8-chloro-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Ethyl 2-morpholinobenzoate prepared in the manner described in Tetrahedron, 53:7557, (1997) was refluxed with 10 N NaOH in tetrahydrofuran-ethanol (8:2) for 1.5 15 hrs to give 2-morpholinobenzoic acid, mp 156-157 0 C. A 1.8 g sample of this compound in 5 ml of CH 2

CI

2 (chilled) was added a solution of 7.9 ml of oxalyl chloride in CH 2 C1 2 (2M) followed by the addition of 0.058 ml of N, N-dimethylformamide. The solution was stirred at room temperature for 6 hrs and the solvent removed. Toluene was added (2 times) and removed to give 2-(4- morpholino)benzoyl chloride as 20 a yellow solid. In the manner described in Reference Examples 181 and 189, the preceding 2 (4-morpholino)benzoyl chloride was reacted with methyl 2-[(2-amino-4-chlorobenzyl) (4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and the product was stirred 25 with NaHCO 3 in methanol to give methyl 4-(4-methoxybenzenesulfonyl)-1-[2-(4 morpholino)phenylcarbonyl]-8-chloro-2,3,4,5-tetrahydro- 1 H- [ 1,4]benzodiazepine-3 carboxylate, as a white solid having a mp 100-105 0 C. To 0.90g of this compound in 10 ml of tetrahydrofuran was added 1.95 ml of 1 30 N NaOH and the solution was stirred at room temperature overnight. Acidification with 2N citric acid gave 0.82 g of solid, mp 136-143 0 C. This compound, 4-(4 methoxybenzenesulfonyl)- 1-[2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid (0.78g) was converted to the potassium salt and reacted first with oxalyl chloride and then with hydroxylamine as 35 described in Example 63 to give 0.276g of product as a light yellow solid, mp 1320 C.

WO 99/37625 PCT/US99/01325 - 107 Example 65 1-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl) -2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide A mixture of 0.270 g of methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5 5 tetrahydro- 1H-[1,4] benzodiazepine-3-carboxylate of Reference Example 12, 0.291 g of 4-ethoxybenzoyl chloride and 500 pl of triethylamine in 5 ml of CH 2 Cl, was stirred at room temperature overnight. The mixture was diluted with CH 2 Cl 2 and H 2 0 and the

CH

2 C1 2 layer was separated and concentrated to dryness. The residue was triturated with ethyl acetate to give 0.276g of methyl 1-(4-ethoxybenzoyl)-4-(4-methoxybenzene 10 sulfonyl)-2,3,4,5tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as white crystals, mp 187-190 0 C. A 0.47 g sample of this compound was hydrolyzed with 1.2 ml of IN NaOH in 4 ml of tetrahydrofuran. Dilution with H 2 0 and acidification with IN HCI gave 0.40 g 15 of the acid as a white solid, mp 144-152 0 C. The preceding compound (0.35g) was converted to the above-titled compound in the manner described in Example 1 to provide 0.195g of solid, mp 136-142 0 C. Example 66 20 4-(4-Methoxybenzenesulfonyl) -1-[2-chloro-4-(3-methyl-1 pyrazolyl)phenylcarbonyl}-2,3,4,5-tetrahydro -1H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide As described in Example 65, methyl 4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-lH-[1,4]benzodiazepine-3-carboxylate was reacted with 4-(3-methyl-1 25 pyrazolyl)-2-chlorobenzoyl chloride to give methyl 4-(4-methoxybenzenesulfonyl)-1 [2-chloro-4-(3-methyl-l-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro-lH-[ 1,4]benzo diazepine-3-carboxylate as a white solid. Anal. for C 29

H

27 C1N 4 0 6 S: Calc'd: C, 58.3; H, 4.6; N, 9.4. Found: C,58.2; H, 4.9; N, 8.9. 30 This compound was hydrolysed with IN NaOH in tetrahydrofuran as described in Reference Example 185 to give the benzodiazepine-3-carboxylic acid derivative as a white solid. This compound was reacted with oxalyl chloride and then reacted with hydroxylamine as described in Example 1 to give the product as white crystals, mp 35 189-191 0

C.

WO 99/37625 PCT/US99/01325 - 108 Example 67 1-Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-te t rah y d r o-1H [1,4]benzodiazepine-3-carboxylic acid, Hydroxylamide A mixture of 1.7 g of the compound of Reference Example 45 and 25 ml of 5 borane in tetrahydrofuran (1.0 Molar) was refluxed under nitrogen overnight. To the solution was added 5 ml of CH 3 OH, CH2Cl2 (40 ml) and 30 ml of 2N HCI and the mixture stirred at room temperature for 1.5 hr. The organic layer was separated, washed with brine, dried with Na2SO4 and the solvent removed. The residue was crystallized from ethanol-hexane to give 1.15g of methyl 1-benzyl-4-(4 10 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylate as white crystals, mp 120-122oC. A sample (1.0 g) of this compound was hydrolysed with 2.8 ml of 1 N NaOH in 7 ml of tetrahydrofuran as described in Reference Example 104 to give 0.64 g of the 2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid derivative as white crystals, mp 183-185 0 C. 15 A 0.55 g sample of this compound was converted to the acid chloride which was reacted with hydroxylamine as described in Example 1 to give the product as a light brown foam; Mass spectrum (ES) 468.1 (M +H). 20 Utilizing the procedure described in Example 65 above, the following compounds may be prepared. Example 68 4-(4-Methoxybenzenesulfonyl)-1-(4-(2-thienyl)phenyl-carbonyl) 25 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide Example 69 4-(4-Methoxybenzenesulfonyl)-l-(4-(3-thienyl)phenyl-carbonyl) 30 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide WO 99/37625 PCT/US99/01325 - 109 Example 70 4-(4-Methoxybenzenesulfonyl)-1-[2-(3-pyrazol)phenyl-carbonyl] 2,3,4,5-tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 5 Example 71 1-(2,4 - Dimethoxybenzoy l)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 10 To a cooled (0°C) solution of 1.0 g (2.66 mmol) of 4-(4 methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylate from Reference Example 12 and 1.85 ml (13.3 mmol) of triethylamine in 8 ml of

CH

2 Cl 2 was added 1.17 g (6.65 mmol) of 2,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature overnight, diluted with CH 2 Cl 2 and washed 15 with 2 N citric acid. The organic layer was washed with H 2 0, 1 N Na 2

CO

3 , brine and dried over Na 2

SO

4 . The solvent was removed and the residue was chromatographed on thick layer silica gel plates with ethyl acetate-hexane (1:1) as an eluent to give 1.0 g of methyl 1-(2,4-dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylate as a white foam. Anal. for 20 C 27

H

28

H

2 0 8 S: Calc'd: C,60.0; H,5.2; N,5.2; Found: C,60.0; H,5.2; N,5.1; Mass Spectrum (ES): 541.0 (M+H). 25 A 0.80 g (1.48 mmol) sample of the preceding compound and 1.92 ml (1.92 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran was stirred at room temperature for 1.5 hours. The solvent was removed and the residue diluted with water. The solution was acidified with 1 N HC1, chilled and filtered to give 0.70 g of 1-(2,4-dimethoxy benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H- [ 1,4]benzodiazepine 30 3-carboxylic acid as a white solid. Anal. for C 2 6

H

26

N

2 0 8 S: Calc'd: C,59.3; H,5.0; N,5.3; Found: C,56.1; H,4.8; N,5.0; Mass Spectrum (ES): 527.0 (M+H). 35 A 0.80 g (1.52 mmol) sample of the preceding compound in 10 ml of CH 2 Cl 2 (chilled to 0OC) was added to 1.52 ml (3.04 mmol) of oxalyl cholride (2.0 M solution in

CH

2 Cl 2 ). To the solution was added 118 pl (1.52 mmol) of N,N-dimethylformamide WO 99/37625 PCT/US99/01325 -110 and the solution stirred at 0OC for 1.5 hours (Mixture A). A mixture of 0.422 g (6.08 mmol) of hydroxylamine hydrochloride, 1.27 ml (9.14 mmol) of triethylamine, 5 ml of N,N-dimethyformamide and 0.5 ml of water was prepared in a separate flask, stirred for 20 minutes at room temperature and then cooled to 0 0 C in an ice bath (Mixture B). 5 The cooled solution of Mixture A was added to the cooled Mixture B and then stirred at room temperature overnight. The mixture was diluted with CH 2 C2 and 2 N citric acid added. The organic layer was separated, washed with H 2 0, brine and dried with Na 2

SO

4 . The solvent was removed and the residue crystalized from ethanol to give 0.40 g of product as white crystals, mp 189-191'C. Anal. for C 26

H

27

N

3 0 8 S: 10 Calc'd: C,57.7; H,5.0; N,7.7; Found: C,57.6; H,4.9; N,7.7; Mass Spectrum (ES): 542.2 (M+H). Example 72 15 4-(4-Methoxybenzenesulfonyl)-1-[2-(4-methylpiperazin-1-yl)acetyl] 2,3,4,5-tetrahydro-1H- [ 1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide To a mixture of 2.5 g (6.64 mmol) of methyl 4-(4-methoxybenzenesulfonyl) 2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate (Reference Example 12) and 20 4.63 ml (33.2 mmol) of triethylamine in 40 ml of CH 2 Cl 2 cooled to O'C was added to 1.65 g (14.63 mmol) of chloroacetyl chloride. The solution was stirred at room temperature for 2 days, chilled to 0OC and 926 p of triethylamine and 750 mg of chloroacetyl chloride were added thereto. The mixture was stirred at room temperature overnight, diluted with CH 2

CI

2 and H 2 0. The insoluble solid was filtered off. The 25 organic layer of the filtrate was separated, washed with brine, dried with Na 2

SO

4 and filtered through diatomaceous earth. The solvent was removed and the residue triturated with ethyl acetate and a trace of ethanol. Chilling and filtering gave 0.75 g of methyl 1-(chloroacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H-[ 1,4] benzodiazepine-3-carboxylate (Reference Example 91). Anal. for C 20

H

2 1 C1N 2 0 6 S: 30 Calc'd: C,53.0; H,4.7; N,6.2; Found: C,51.6; H,4.6; N,5.7; Mass Spectrum (ES): 453.0 (M+H). To a solution of 1.4 g (3.09 mmol) of the preceding compound in 12 ml of 35 CH 2

CI

2 cooled to 0OC was added 1.2 ml (6.79 mmol) of N,N-diisopropylethylamine followed by the addition of 753.2 pl (6.79 mmol) of 1-methylpiperazine. The mixture was stirred at room temperature overnight, diluted with CH 2 Cl 2 , and washed with 2 N WO 99/37625 PCT/US99/01325 -111 citric acid, H 2 0, 1 M NaHCO 3 , brine and dried (Na,2SO 4 ). The citric acid wash was made basic with saturated NaHCO 3 and then extracted with CH2C1 2 . The extract was dried over Na 2

SO

4 and the solvent removed under vacuum to give 1.10 g of methyl 4 (4-methoxybenzenesulfonyl)- 1-[2-(4-methylpiperazin- 1 -yl)acetyl]-2,3,4,5-tetrahydro 5 1H-[1,4]benzodiazepine-3-carboxylate as a white glass. A mixture of 1.0 g (1.94 mmol) of the preceding compound and 2.3 ml (2.3 mmol) of 1 N KOH in 5 ml of methanol was stirred at room temperature for 2 hours. The solvent was removed under vacuum. To the residue was added toluene (2 times) 10 and the solvent removed under vacuum after each addition. The solid was dried at 65°C under vacuum for 6 hours to give 1.1 g of potassium 4-(4-methoxybenzenesulfonyl)-1 [2-(4-methylpiperazin-1-yl)acetyl]-2,3,4,5-tetrahydro- 1 H-[1,4]benzodiazepine-3 carboxylate as a white solid. 15 To 1.85 ml (3.69 mmol) of a 2.0 molar solution of oxalyl chloride in CH 2

CI

2 , cooled to O'C, was added slowly 286 pl (3.69 mmol) of N,N-dimethylformamide (precipitate formed). To this stirred mixture was 1.0 g (1.85 mmol) of the preceding compound in 5 ml of CH 2 Cl 2 . The mixture was stirred under nitrogen for two hours (Mixture A). 20 In a separate flask, a mixture of 0.514 g (7.4 mmol) of hydroxylamine hydrochloride, 1.55 ml (11.1 mmol) of triethylamine in tetrahydrofuran-water (4:1) was stirred at room temperature and then cooled to 0°C and stirred for 5 minutes. To this mixture was added the cooled (0°C) Mixture A and then the resulting solution 25 stirred at room temperature overnight. The mixture was concentrated under vacuum and CH 2

CI

2 added. The organic layer was separated and concentrated to dryness to give 1.4 g of product. The product was chromatographed on thick layer silica gel plates with CH 2

CI

2

-CH

3

OH-NH

4 OH(45:6:1) as a solvent to give 65 mg of brown solid: Mass Spectrum (ES): 518.3 (M + H). 30 WO 99/37625 PCT/US99/01325 - 112 Example 73 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(methoxyacetyl)-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 5 A. N-[4-(4-Chlorophenyloxybenzenesulfonyl)serine, methyl ester (methyl 3-hydroxy-2-[4-(4-chlorophenoxy)benzenesulonylaminolpropionate). To a mixture of 3.42 g (22 mmol) of serine, methyl ester, hydrochloride and 10.7 ml (77.0 mmol) of triethylamine in 60 ml of CH 2 Cl 2 , chilled to O'C, was added 6.063 g (20 mmol) of 4 (4-chlorophenyloxy)benzenesulfonyl chloride. The mixture was stirred at room 10 temperature overnight, diluted with CH 2 C12 and washed with 2 N citric acid, H 2 0, 1 N NaHCO 3 , brine and dried with Na 2

SO

4 . The solvent was removed to give an oil which was dried under vacuum at 68°C to give a solid. Trituration with hexane-ethyl acetate gave 5.85 g of off-white crystals, mp 90-94°C. Anal. for CI 6

HI

6 C1NO 6 S: Calc'd: C,49.8; H,4.2; N,3.6; 15 Found: C,50.1; H,4.1; N,3.8; Mass Spectrum (ES): 385.9 (M+H). B. Methyl 3-hvdroxy-2- { [4-(4-chlorophenyloxy)benzene-sulfonyl]l-(2 nitrobenzyl)amino}proprionate. To a cooled (0°C) solution of 5.5 g (14.76 mmol) of 20 compound from part A in 60 ml of dry N,N-dimethylformamide was added (portionwise), 0.682 g (17 mmol) of sodium hydride (60% in oil). After gas evolution ceased, 3.7 g (17 mmol) of 2-nitrobenzylbromide in 15 ml of N,N-dimethylformamide was added slowly. The mixture was stirred at room temperature overnight and diluted with 200 ml of ethyl acetate and 150 ml of water. The organic layer was separated and 25 washed with H 2 0, brine and dried with Na 2

SO

4 . The solvent was removed under vacuum and the residue chromatographed on a silica gel column with hexane-ethyl acetate (2:1) as an eluent to give 4.7 g of a brown oil. Anal. for C 23

H

2 1 C1N 2 0 8 S: Calc'd: C,53.0; H,4.1; N,5.4; Found: C,53.2; H,4.2; N,5.1; 30 Mass Spectrum (ES): 521.2 (M+H). C. Methyl 2- { (2-aminobenzyl)-[4-(4-chlorophenyloxy)benzene sulfonyllamino}-3-hydroxypropionate. A mixture of 3.0 g (5.77 mmol) of the compound from part B and 0.300 g of 10% wet palladium on carbon (50% in H 2 0) in 35 300 ml of ethyl acetate-ethanol (1:1) was shaken in a Parr hydrogenator under 35 psi of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the WO 99/37625 PCT/US99/01325 - 113 solvent removed under vacuum. The residue was dried at 65°C under vacuum to give 2.63 g of an off-white solid. Anal. for C 23

H

23 C1N 2 0 6 S: Calc'd: C,56.3; H,4.7; N,5.7; Found: C,56.6; H,4.6; N,5.6; 5 Mass Spectrum (ES): 491.1 (M+H). D. Methyl 2- { [4-(4-chlorophenyloxy)benzenesulfonyll- [2-(methoxy acetylamino)benzyl]amino } acrylate. To a mixture of 0.80 g (1.63 mmol) of the compound from Part C and 1.14 ml (8.15 mmol) of triethylamine in 8 ml of CH 2 C1 2 , 10 cooled to 0°C, was added 328 pl (3.58 mmol) of methoxyacetyl chloride. The mixture was stirred at room temperature overnight, diluted with CH 2

CI

2 and washed with H 2 0, 2 N citric acid, brine and dried (Na 2

SO

4 ). The solvent was removed under vacuum and the residue chromatographed on thick layer silica gel plates with hexane-ethylacetate (2:1) as a solvent to give 0.48 g of a white foam. Anal. for C 26

H

25 C1N 2 0 7 S: 15 Calc'd: C,57.3; H,4.6; N,5.1; Found: C,56.7; H,4.7; N,5.0; Mass Spectrum (ES): 545.2 (M+H). E. Methyl 4-[4-(4-chlorophenyloxy)benzenesulfonyll-1-(methoxyacetyl) 20 2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate. A mixture of 0.45 g (0.827 mmol) of the compound from part D and 0.09 g of anhydrous NaHCO 3 in 5 ml of dry methanol was stirred at room temperature overnight. The solvent was removed, ethyl acetate added and the mixture washed with H 2 0, brine and dried with Na 2

SO

4 . The solvent was removed to give 0.43 g of an off-white solid. Anal. for C 26

H

25 C1N 2 0 7 S: 25 Calc'd: C,57.3; H,4.6; N,5.1; Found: C,57.6; H,4.6; N,5.0; Mass Spectrum (ES): 545.2 (M+H). F. 4-[(4-Chlorophenyloxy)benzenesulfonvl]l- I -(methoxyacetyl)-2.3.4.5 30 tetrahydro-1H-[1,41benzodiazepine-3-carboxylic acid. A mixture of 0.52g (0.956 mmol) of the compound from Part F and 1.2 ml (1.2 mmol) of IN KOH in 8 ml of methanol was stirred at room temperature for 2 hours. An additional 0.6 ml of IN KOH was added and the mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with H20 and extracted with ethyl acetate. The 35 extract was washed with brine and dried over Na 2

SO

4 . The solvent was removed and the product dried at 65°C under vacuum to give 0.49 g of off-white foam. Anal. for

C

25

H

23 C1N 2 0 7

S:

WO 99/37625 PCT/US99/01325 -114 Calc'd: C,56.6; H,4.4; N,5.3; Found: C,56.6; H,4.3; N,5.0; Mass Spectrum (ES): 531.2 (M+H). 5 To a solution of 0.45 g (0.848 mmol) of the compound from Part F in 4 ml of

CH

2 Cl 2 cooled to 0°C was added 850 pl (1.69 mmol) of oxalyl chloride (2.0 molar solution in CH2Cl 2 ) and then 50.2 pl (0.848 mmol) of N,N-dimethylflormamide. This mixture was stirred under nitrogen for 2 hours (Solution A). In a separate flask a mixture of 2.12 g (5.0 mmol) of hydroxylamine hydrochloride, 1.07 ml (7.65 mmol) 10 of triethylamine, 4 ml of tetrahydroforan and 0.4 ml of H 2 0 was stirred for 15 minutes and cooled to 0 0 C. To this mixture was added the cooled (0 0 C) Solution A and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum, diluted with ethyl acetate and washed with H 2 0, 1N NaHCO 3 2 N citric acid, brine and dried over Na 2

SO

4 . The solvent was removed under vacuum and the 15 residue chromatographed on thick layer silica gel plates with 2% methanol in ethyl acetate to give 0.20 g of the product of the Example as a brown solid. Anal. for

C

25

H

24 C1N 3 0 7 S: Calc'd: C,55.0; H,4.4; N,7.7; Found: C,53.1; H,5.0; N,6.7; 20 Mass Spectrum (ES): 546.3 (M+H). Example 74 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1l-(2-thienylcarbonyl) 2,3,4,5-tetrahydro-1H[1,4]benzodiazepine-3-carboxylic acid, 25 Hydroxyamide The following reactions were carried out in the manner described for Example 73, Parts D, E, and F. A 1.4 g (2.85 mmol) sample of methyl 2-{(2-aminobenzyl)-[4 (4-chlorophenyloxy)benzenesulfonyl]amino}-3-hydroxypropionate (the compound of Part C of Example 73) was reacted with 1.25 g (8.55 mmol) of 2-thiophenecarbonyl 30 chloride to give 1.7 g of methyl 2-{ [4-(4-chlorophenyloxy)benzyenesulfonyl]-[2-(2 thienylcarbonyl-amino)benzyl]amino } acrylate as a yellow oil. Mass Spectrum (ES): 583.1 (M+H). The reaction of 1.5 g of the preceding compound with 0.251 g of NaHCO 3 in 8 35 ml methanol gave 1.6 g of methyl 4-[4-(4-chlorophenyloxy)benzenesulfonyl)-1-(2 thienylcarbonyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate as a yellow oil.

WO 99/37625 PCT/US99/01325 - 115 Mass Spectrum (ES): 583.1 (M+H). The hydrolysis of 1.5 g of the preceding compound with 3.3 ml of 1 N NaOH in 6 ml of tetrahydroforan gave 1.2 g of 4-[4-(4-chlorophenyloxy)benzenesulfonyl]-1 5 (2-thienylcarbonyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylic acid as an off-white foam. As described for Example 73, 1.0 g of the preceding benzodiazepine 3-carboxylic acid was reacted with oxalyl chloride and then with hydroxylamine to give the product of the Example as a solid (off-white foam). Mass Spectrum (ES): 584.2 (M+H). 10 Example 75 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1- (benzoyl)-2,3,4,5 tetrahydro-1H[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 15 The following reactions were carried out in the manner described for Example 73, Parts D, E, and F. A 1.0 g (2.04 mmol) sample compound C of Example 73 was reacted with 710 pl (6.10 mmol) of benzoyl chloride to give 1.25 g of methyl 2-{ [4-(4 chlorophenyloxy)benzenesulfonyl]-[2-(benzoylamino)benzyl]amino } acrylate as a brown oil. 20 Mass Spectrum (ES): 577.2 (M+H). The reaction of 1.1 g (1.9 mmol) of the preceding compound with 0.208 g (2.48 mmol) of NaHCO 3 in 8 ml of methanol gave 1.1 g of methyl 4-[4-(4 chlorophenyloxy)benzenesulfonyl]- 1-(benzoyl)-2,3,4,5-tetrahydro- 1H 25 [1,4]benzodiazepine-3-carboxylate as a brown oil. Mass Spectrum (ES): 577.1 (M+H). A 1.0 g (1.73 mmol) sample of the preceding compound was hydrolysed with 2.3 ml (2.75 mmol) of 1 N NaOH in 5 ml of tetrahydrofuran to give 0.50 g of 4-[4-(4 30 chlorophenyloxy)benzenesulfonyl]- 1 -(benzoyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid as a white foam. As described for Example 73, 0.460 g (0.817 mmol) of the preceding benzodiazepine-3-carboxylic acid was reacted with oxalyl chloride and then with hydroxylamine to give 0.04 g of the product of the Example as a light brown solid. 35 Mass Spectrum (ES): 578.2 (M+H).

WO 99/37625 PCT/US99/01325 -116 Example 76 4-[4-(4-Pyridinyloxy)benzenesulfonyl] -- -(met hoxyacetyl)-2,3,4,5 tetrahydro-1H[1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide 5 A. To a cooled mixture of 6.84 g (44 mmol) of D, L-serine, methyl ester hydrochloride and 21.4 (144 mmol) of triethylamine in 90 ml of CH 2 Cl 2 was added a solution of 10.78 g (40 mmol) of 4-(4-pyridinyloxy)benzenesulfonyl chloride in 50 ml of CH 2 Cl 2 . The mixture was stirred at room temperature overnight, diluted with 50 ml of CH 2 Cl 2 and the solution washed with H 2 0, 1N NaHCO 3 , 2 N citric acid, brine and 10 dried (with Na 2

SO

4 ). The solvent was removed under vacuum to give a solid. The aqueous 2 N citric acid wash was made basic with saturated NaHCO 3 and then extracted with CH 2 Cl 2 . The solvent was removed to give a solid. The two crops of solid were combined, washed with H 2 0 and then hexane. The solid was dried at 80'C to give 10.95 g of methyl 3-hydroxy-2-[4-(4-pyridinyloxy)-benzenesulfonylamino] 15 propionate as white crystals, mp. 137-139°C. B. To a solution of 4.5 g (12,.78 mmol) of the product from Part A in 35 ml of dry N,N-dimethylformamide cooled to 0°C was added (portionwise) 0.662 g (16.61 mmol) of NaHCO 3 (60% in oil). The mixture was stirred 15 minutes and 3.59 20 g (16.61 mmol) of 2-nitrobenzylbromide in 15 ml of N,N-dimethylformamide was added hereto. The mixture was stirred at room temperature overnight, diluted with ethyl acetate (200 ml) and H 2 0 (100 ml). The organic layer was separated and washed with H 2 0, brine and dried (with Na 2

SO

4 ). The solvent was removed to give 5.9 g of solid. Column chromatography on silica gel with ethyl acetate-hexane (10:1) as an 25 eluant gave 1.4 g of methyl 2- { (2-nitrobenzyl)-[4-(4-pyridinyloxy) benzenesulfonyl] amino }-3-hydroxypropionate as an off-white solid. Mass Spectrum (ES): 488.1 (M+H). The compound from Part B was converted to the product of the Example in the 30 manner described for Example 73 in Parts D, E, and F.

WO 99/37625 PCT/US99/01325 -117 Example 77 1-(Benzoyl)-4-(4-pentyloxybenzenesulfonyl)-2,3,4,5-tetrahydro-lH [1,4]-benzodiazepine-3-carboxylic Acid, Hydroxyamide To a stirred solution of 1.24 g (4.82 mmol) of triphenylphosphine in 12 ml of 5 toluene and 3 ml of N,N-dimethylformamide was added 524 gL (4.82 mmol) of 1 pentanol and 1.5 g (3.22 mmol) of methyl 1-(benzoyl)-4-(4-hydroxybenzenesulfonyl) 2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylate. To this stirred mixture was added 259 IlL (4.82 mmol) of diethyl azodicarboxylate and the mixture was stirred overnight. The solvent was removed and the residue chromatographed on silica gel 10 with ethyl acetate-hexane (1:3) as solvent. Concentration of the fractions containing product gave 1.59 g of a white solid; mp 170-172°C; Anal. Calcd for C 29

H

32

N

2 0 6 : C, 64.9; H, 6.0; N, 5.2. Found: C, 64.7; H, 6.0; H, 5.4. A mixture of a 1.4 g (2.61 mmol) sample of the preceding compound and 3.4 15 ml (3.4 mmol) of 1N KOH in 7 ml of tetrahydrofuran was stirred at room temperature for 2 hrs and the solvent removed under vacuum. To the residue was added toluene and the solvent removed (repeated two times). The residue was dried at 85°C under vacuum overnight to give 1.5 g of 1-(benzoyl)-4-(4-pentyloxybenzenesulfonyl) 2,3,4,5- tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid as the potassium salt. 20 To 10 ml of CH 2

CI

2 was added 4.8 ml (9.6 mmol) of oxalyl chloride in CH 2

CI

2 (2.0 molar) and the solution chilled to 0'C. To the chilled solution was added 740 [tL (9.56 mmol) of N,N-dimethylformamide and 1.34g (2.39 mmol) of the preceding potassuim salt in 5 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 1.5 hr, cooled to 0°C ,and added to a chilled (0°C) solution of 2.2 ml 25 (35.9 mmol) of 50% aqueous hydroxylamine in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature overnight and diluted with CH 2 C12. The CH 2 Cl 2 layer was separated, washed with H 2 0 and concentrated to dryness under vacuum. The residue was chromatographed on silica gel with ethyl acetate-hexane (1:1) as solvent. Fraction containing product was concentrated to dryness and the residue dissolved in 30 ethyl acetate. The solution was washed with three times with H 2 0 and once with brine and dried (Na 2

SO

4 ). The solvent was removed and the residue dried at 85C under vacuum overnight to give 0.96 g of product as a white foam; Mass spectrum (ES) 538.0 (M+H).

WO 99/37625 PCT/US99/01325 -118 Example 78 1-Acetyl-4-(4-Hydroxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, Hydroxyamide To a crude mixture of 1-acetyl-4-(4-hydroxybenzenesulfonyl)-2,3,4,5 5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid (0.55g) and N-hydroxy benzotriazole (0.414g) in 5 ml of N,N-dimethylformamide was added 0.684 g of 1-[3 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred at room temperature for 1 hr and then 750 gtL of hydroxylamine in water (50%) was added and the mixture stirred at room temperature overnight. The mixture was diluted 10 with ethyl acetate and then washed with H 2 0, 2N citric acid, brine and dried (Na 2

SO

4 ). The solvent was removed under vacuum to give a solid. Chromatography on silica gel with 10% methanol in ethyl acetate as solvent gave a solid which was dried at 78'C under vacuum overnight to give an off-white foam; Mass spectrum (ES) 406.1 (M+H); Anal. Calcd. For ClgH I9

N

3 0 6 S; C, 53.3; H, 4.7; N, 10.4. Found: C, 52.6; H, 5.2; N, 15 10.4. The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as 20 indicating the scope of the invention.

Claims (6)

1. A compound of Formula 1: 0 II SO2 R4 HOHN N RR R R 2 N I R3 5 1 wherein R is selected from hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , 10 -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen; R 4 is hydroxy, (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, -RI ,
7- R I O_ I R 0 S - N N , - -S 0-N N - -R ,- S-R ,or R wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; R 1 and R 2 are each, independently, hydrogen or CH 3 : 15 R 3 is (C 1 - C 8 )alkyl, NH 2 CH 2 CO-, (C 1 - C6)alkylNHCH 2 CO-, HO(CH 2 )mCO-, HCO-, Aryl(CH 2 )nCO-, Heteroaryl(CH 2 )nCO-, (C 1 - C 3 )alkyl-O-(CH 2 )nCO-, (C 1 - C 3 )alkylCO-, (C 1 - C 3 )alkylCO-NHCH 2 CO-, (C 3 - C 7 )cycloalkylCO-, (C 1 - C 3 )alkylSO 2 -, Aryl(CH 2 )nSO 2 -, Heteroaryl(CH 2 )nSO 2 -, (Cl - C 3 )alkyl-O (CH 2 )m-SO2-, (Cl - C 3 )alkyl-O-(CH 2 )m, (C 1 - C 3 )alkyl-O-(C 1 - C 3 )alkyl-O-(C 1 - C 3 )- WO 99/37625 PCT/US99/0 1325 - 120 alkyl, HO-(Cl - C 3 )alkyl-O-(C 1 - C 3 )alkyl. Aryl-O-CH 2 CO-, Heteroaryl-O-CH 2 CO-, Ary1CH=CHCO-, HeteroatiylCH=CHCO-, (C 1 - C 3 )alkylCH=CHCO-. 0 CH 2 0C- 0 CH 2 0C NHCH,CO 5 Aryl(C 1 - C 3 )alkyl, Heteroaryl(C 1 -C 3 )alkyl, AryICH=CHCH 2 -, HeteroarylCH=CHCH 2 -, (C 1 I C 6 )alkylCH=CHCH 2 -, 10 CO-/ w 15 R'OCH 2 CH(OR')CO-, (R'OCH2) 2 C(R')CO-, CH3-\-i(Cl- C 3 )alkylCH=CH-CO- 0\Q-2N (C I - C 6 )alkylCO C- C 6 )alkyICO- (C - C 3 )alky1CONHCO., [N-(C-C 6 )akyCO (;N(C I - C 6 )alkylCO- /N(,C)aklO , 1N(CI -C 6 )alkylCO N CH 3 NN(C 1 - C 6 alkylCO- ,t-Boc-N N-(Cl - C 6 )alkylCO-' R 0- 0 EtOC ~,N(Cl - C 6 )alkylCO- WO 99/37625 PCT/US99/01325 - 121 - (C - C 6 )alkylCO- R O CH 3 R' 0 CO [(C 1 - C 6 )alkyl] 2 -N-(C 1 - C 6 )alkyl CO-, or (C 1 - C 6 )alkyl-NH-(C 1 - C 6 )alkylCO-; 5 wherein m= Ito3;n=0to3; Aryl is X I and R Heteroaryl is 10 _ 4x 4x N;7 S 0 x ~N -X, X~s Xo X7 N O S R' N , NX ,or X 0 N N I I R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 , and R and R' are as defined above; 15 L is hydrogen, (C 1 -C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , -NH-(C l C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, CON Y CONH- Y CONH CONH- , or or /S 0 WO 99/37625 PCT/US99/01325 - 122 M is ,- Y Y N S 0 N N N R' N N N II I R' I ' R'- N N- ,OCO-N N, Z N tBoc -N N- 0 N- DN 5 N- , or N(R')(R') where R' is as defined above; W is O, S, NH or N(C 1 - C 3 )alkyl; Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C 1 - C 3 )alkyl, O-(C l - C 3 )alkyl, or -CH 2 OH; and pharmaceutically acceptable salts thereof. WO 99/37625 PCT/US99/01325 - 123 2. A compound according to claim 1, wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , NH(C I - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C - C 3 )alkyl, wherein R' 5 is (C 1 - C 3 ) alkyl or hydrogen; R 4 is (C 1 - C 6 ) alkyl-O-, (C I - C 6 ) alkyl-S-, - R ,-- RI R 1 1 -0 N N , -. RS-, N N - /R , SR ,or -- R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; R 1 and R 2 are each, independently, hydrogen or CH 3 ; R 3 is (C 1 - C 8 )alkyl, NH 2 CH 2 CO-, (C 1 - C 6 )alkylNHCH 2 CO-, HO(CH 2 )mCO- , 10 HCO-, Aryl(CH 2 )nCO-, Heteroaryl(CH 2 )nCO-, (C 1 - C 3 )alkyl-O-(CH 2 )nCO-, (C 1 - C 3 )alkylCO-, (C 1 - C 3 )alkylCO-NHCH 2 CO-, (C 3 - C 7 )cycloalkylCO-, Aryl-O-CH 2 CO-, HeteroarylOCH 2 CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C 1 - C 3 )alkylCH=CHCO-, 0 0 - CH 2 OC- , or CH 2 OC-NHCH 2 CO 15 wherein m= I to3; n = 0 to 3; Aryl is X and R' WO 99/37625 PCT/US99/01325 - 124 Heteroaryl is x x /, Xr, X X -x >5 N 0 S I R' k N , N ,or X O N N I I R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 wherein R and R' are as 5 defined above; and pharmaceutically acceptable salts thereof. 3. A compound according to claim 1, wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , 10 -OCF 3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen; R 4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, - R , -_ RI /RI R R 0-0 0-0 -- _ , X N , ,, , R , -- S ' R N N - OR , - SR or -- R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; 15 R 1 and R 2 are each, independently, hydrogen or CH 3 ; WO 99/37625 PCT/US99/01325 - 125 R 3 is CH 3 N(CI - C 3 )alkylCH=CH-CO- , 0 N-(CI - C 6 )alkylCO N-(CI - C 6 )alkylCO- , (C 1 - C 3 )alkylCONHCO-, N-(C-C 6 )alkylCO C N-(C 1- C 6 )alkylCO- C N-(Cl-C 6 )alkylCO- , N-(Cl-C6)alkylCO CH 3 - N (C 1 - C 6 )alkylCO- , t-Boc-N N-(C 1 - C0 6 )alkylCO-, C0- 0 EtOC N(CI - C 6 )alkylCO RO R' 0R' N- (CI - C 6 )alkylCO- R O R' CH 3 R' O CO 5 [(C 1 - C 6 )alkyl] 2 -N-(C 1 - C 6 )alkyl CO-, or (C 1 - C 6 )alkyl-NH-(Cl - C 6 )alkylCO-, where R' is as defined above; and pharmaceutically acceptable salts thereof. 10 4. A compound according to claim 1, wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C3) alkyl or hydrogen; WO 99/37625 PCT/US99/01325 - 126 R 4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-. - , -S , N N -& R ,-R , or -&R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; R 1 and R 2 are each, independently, hydrogen or CH 3 ; 5 R 3 is (C 1 - C 3 )alkylSO 2 -, Aryl(CH2)nSO 2 -, Heteroaryl(CH2)nSO 2 -, or (C 1 - C 3 )alkyl O-(CH 2 )m-SO 2 , wherein m= 1 to 3; n = 0 to 3; Aryl is X and 10 R' Heteroaryl is XX X X N S 0 I R' N , NX , or X 0 N N I I R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 and R and R' are as defined 15 above; and pharmaceutically acceptable salts thereof. WO 99/37625 PCT/US99/01325 - 127 5. A compound according to claim 1, wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F. NH 2 , 5 NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (C 1 - C 3 ) alkyl or hydrogen; R 4 is (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, -, -R , , R , 0 S I R RN I RR1YI - N N , -- -S NN N -R , SR , or R, wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; 10 R 1 and R 2 are each, independently, hydrogen or CH 3 ; R 3 is (C 1 - C 8 )alkyl, Aryl(C 1 - C 3 )alkyl, Heteroaryl(C 1 - C 3 )alkyl, ArylCH=CHCH 2 , HeteroarylCH=CHCH 2 -, or (C - C 6 )alkylCH=CHCH 2 -, wherein Aryl is X 15and 15 R' WO 99/37625 PCT/US99/01325 - 128 Heteroaryl is -l., X .X 5X X N S 0 xN \r,- N I N N N R' N , N , or X O N N I I R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 and R and R' are is as 5 defined above; and pharmaceutically acceptable salts thereof. 6. A compound according to claim 1, wherein R is hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , 10 NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), or -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is (CI - C 3 ) alkyl or hydrogen; R 4 is (C 1 - C 6 ) alkyl-0-, (C 1 - C 6 ) alkyl-S-, -0 R0 , -S0 -,,$ R / RI <YRl - R -0 N N , -0- -S N N - OR , - SR , or R ,wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 : 15 R 1 and R 2 are each, independently, hydrogen or CH 3 ; WO 99/37625 PCT/US99/01325 - 129 R 3 is L CO- , CO-CO -- X"N M M CO- CO- C CO _Y 1"" y N M Y_ CO 5 CO- Y- - CO wherein m= I to3;n=0to3; L is hydrogen, (C 1 - C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , 10 -NH-(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(Cl - C 3 )alkyl, XCN y CONH- Y CONH ,or Y /4 S0 M is 15 Y -N S , N N , N N N IR' I I' R' I, WO 99/37625 PCT/US99/01325 - 130 R'-N N- OCO-N N ,N tBoc - N N- , 0 N- N S N- , or N(R')(R') where R' is as defined above; W is O, S. NH or N(C l - C 3 )alkyl; Y is hydrogen, F, Cl. CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C 1 - C 3 )alkyl, O-(C 1 - C 3 )alkyl, or -CH 2 OH: and pharmaceutically acceptable salts thereof. 5 7. A compound as claimed in any one of Claims 1 to 6 which is selected from 4-(4-Methoxybenzenesulfonyl)- 1-(3-trifluoromethylbenzoyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 10 4-(4-Methoxybenzenesulfonyl)- 1-(4-methylphenylsulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1 -(Methanesulfonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H 15 [ 1,4]benzodiazepine-3-carboxylic acid, hydroxyamnide, 1,4-Bis-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H- [ 1,4]benzodiazepine-3 carboxylic acid, hydroxyamrnide, 20 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H-[1,4]benzodiazepine 3-carboxylic acid, hydroxyamide, 1 -Acetyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H-[1,4]benzodiazepine-3 carboxylic acid, hydroxyamide, 25 4-(4-Methoxybenzenesulfonyl)- I -(3-pyridinylcarbonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, WO 99/37625 PCT/UJS99/01325 - 131 4-(4-Methoxybenzenesulfonyl)- 1-(2-thienylcarbonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamrnide, I -Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-2,3,.4,5-tetrahydro- I H 5 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide. 4-(4-Methoxybenzenesulfonyl)- 1 -(propane-I -sulfonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 10 4-(4-Methoxybenzenesulfonyl)- 1 -(2-methyl-5-fluorobenzoyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- 1-(4-pyridinylcarbonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 15 4-(4-Methoxybenzenesulfonyl)- 1-(3-phenylpropionyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1 -([1, '-Biphenyl]-2-carbonyl)-4-(4-methoxybenzene-sulfonyl)-2,3,4,5-tetrahydro 20 1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Biphenylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 25 1-(3-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- I -(2-methyl-3-fluorobenzoyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 30 4-(4-Methoxybenzenesulfonyl)- 1 -(2-methyl-3-trifluoromethylbenzoyl)-2,3,4,5 tetrahydro- I H-[ 1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Chloro-6-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 35 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, WO 99/37625 PCT/US99/01325 - 132 1-(4-Fluoro-2-trifluoromethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5 tetrahydro- 1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamrnide, 1-(2-Fluoro-6-trifluoromethylbenzoyl)-4-(4-mnethoxybenzenesulfonyl)-2,3,4,5 5 tetrahydro- 1 H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide. 4-(4-Methoxybenzenesulfonyl)- 1-(2-methylbenzoyl)-2,3,4,5-tetrahydro- 1H [1.4]benzodiazepine-3-carboxylic acid, hydroxyamide, 10 4-(4-Methoxybenzenesulfonyl)- I -(2-methyl-6-chlorobenzoyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,4-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 15 1 -(2,5-Dimethylbenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1 -(2-Chloro-4-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H 20 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, I -(2-Chlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 25 1-(2-Fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1 -(2-Chloro-6-fluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 30 1-(2,3-Difluorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2,4-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H 35 [ 1,4]benzodiazepine-3-carboxylic acid, hydroxyanmide, WO 99/37625 PCT/US99/01325 - 133 1-(2.3-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamnide, 1 -(2,5-Dichlorobenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H 5 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(2-Methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 10 1-(4-Chloro-2-methoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- 1-(2-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 15 4-(4-Methoxybenzenesulfonyl)- 1-(3-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- 1-(4-methyl-2-thienylcarbonyl)-2,3,4,5-tetrahydro- 1 H 20 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(3-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 25 1-(2-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- I -(3-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 30 4-(4-Methoxybenzenesulfonyl)- -(4-methyl-2-furanylcarbonyl)-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(5-Chloro-2-furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H 35 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, WO 99/37625 PCT/US99/01325 - 134 1-(5-Chloro-2-thienylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2.3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, I -Propionyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H 5 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide. 1 -Hexanoyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid. hydroxyamide, 10 1-(3-Methoxypropionyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- 1 -(3-thienylcarbonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 15 1 -(3-Furanylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(trans-Crotonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H 20 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1 -(Methacryloyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 25 1-(Acetylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydyro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1 -(Aminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 30 1 -(N,N-Dimethylaminoacetyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cyclopropylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H 35 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, WO 99/37625 PCT/US99/01325 - 135 4-(4-Methoxybenzenesulfonyl)- 1-(4-(2-thienyl)phenyl-carbonyl)-2.3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl )- I -(4-(3-thienyl)phenylcarbonyl)-2,3,4,5-tetrahydro 5 1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)-I-[2-( 1-pyrazolyl)phenylcarbonyl]-2.3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 10 4-(4-Methoxybenzenesulfonyl)- 1-[2-(3-pyrazolyl)phenylcarbonyl]-2,3,4,5-tetrahydro 1H-[ 1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(Cycloyhexylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1 H-[1,4] benzodiazepine-3-carboxylic acid, hydroxyamide, 15 1 -Methoxyacetyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- 1H [1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 1-Benzoyl-4-(4-methoxybenzenesulfonyl)-7-methyl-2,3,4,5-tetrahydro- 1 H- [1,4] 20 benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- 1 -[(4-trifluoromethoxy)benzoyl]-8-chloro-2,3,4,5 tetrahydro-1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 25 4-(4-methoxybenzenesulfonyl)- 1-[2-chloro-4-(3-methyl- I -pyrazolyl)phenylcarbonyl] 2,3,4,5-tetrahydro- 1 H[1,4]-benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- 1 -[2-( 1 -pyrazolyl)phenylcarbonyl]-7-methyl-2,3,4,5 tetrahydro- IH-[1,4]benzodiazepene-3-carboxylic acid, hydroxyamide, 30 4-(4-Methoxybenzenesulfonyl)- 1- [2-(4-morpholino)phenylcarbonyl]-8-chloro-2,3,4,5 tetrahydro- 1H-[ 1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 1-(4-Ethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H 35 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, WO 99/37625 PCT/US99/01325 - 136 1 -(Cyclobutylcarbonyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-(4-Methoxybenzenesulfonyl)- I -(phenoxyacetyl)-2,3,4,5-tetrahydro- 1 H 5 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide. 4-(4-Methoxybenzenesulfonyl)-1 -(2-methoxyethyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 10 1 -Benzyl-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- I H-[ 1,4]benzodiazepine 3-carboxylic acid, hydroxyamide, 1-(2.4-Dimethoxybenzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 15 4-(4-Methoxybenzenesulfonyl)- I -[2-(4-methylpiperazin- 1 -yl)acetyl]-2,3,4,5 tetrahydro- I H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl] -1 -(methoxyacetal)-2,3,4,5-tetrahydro- 1 H 20 [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]- I -(2-thienylcarbonyl)-2,3,4,5-tetrahydro 1H-[1,4]benzodiazepine-3-carboxylic acid, hydroxyamide, 25 4-[4-(4-Chlorophenyloxy)benzenesulfonyl]-1-(benzoyl-2,3,4,5-tetrahydro-1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide and 4-[4-(4-Pyridinyloxy)benzenesulfonyl]-1 -(methoxyacetyl)-2,3,4,5-tetrahydro- 1H [1,4]benzodiazepine-3-carboxylic acid, hydroxyamide. 30 WO 99/37625 PCT/US99/01325 - 137
8. A pharmaceutical composition comprising a compound of Formula 1 O II SO2 R4 HOHNR N RR R R 2 N 1 wherein 5 R is selected from hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(Cl - C 3 )alkyl, wherein R' is (C 1 - C3) alkyl or hydrogen: R 4 is hydroxy (C 1 - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, - R ,- R RI RI R --- RN N S,--O --- R" S N N - /, S-R , or 10 R wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; R 1 and R 2 are each, independently, hydrogen or CH 3 ; R 3 is (C l - C 8 )alkyl, NH 2 CH 2 CO-, (C 1 - C 6 )alkylNHCH 2 CO-, HO(CH 2 )mCO-, HCO-, Aryl(CH 2 )nCO-, Heteroaryl(CH 2 )nCO-, (C 1 - C 3 )alkyl-O-(CH 2 )nCO-, (C 1 - C 3 )alkylCO-, (C 1 - C 3 )alkylCO-NHCH 2 CO-, (C 3 - C 7 )cycloalkylCO-, 15 (C 1 - C 3 )alkylSO 2 -, Aryl(CH 2 )nSO 2 -, Heteroaryl(CH 2 )nSO 2 -, (C 1 - C 3 )alkyl-O (CH 2 )m-SO 2 -, (C 1 - C 3 )alkyl-O-(CH 2 )m, (C 1 -C 3 )alkyl-O-(Cl-C 3 )alkyl-O-(C 1 -C 3 ) alkyl, HO-(C 1 - C 3 )alkyl-O-(C 1 - C 3 )alkyl, Aryl-O-CH 2 CO-, Heteroaryl-O-CH 2 CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C 1 - C 3 )alkylCH=CHCO-, WO 99/37625 PCT/UJS99/01325 - 138 01 0 O-"CH2OC- K CHOC-NHCHCO Aryl(C 1 - C 3 )alkyl, Heteroaryl(Cl - C 3 )alkyl, Ary]CH=CHCH 2 -. 5 HeteroarylCH=CHCH 2 -, (C 1 I C 6 )alkylCH=CHCH 2 -, yy co-(I - CO M N M ,Co co-~ co- Y-F a7C0 R-OCH 2 CH(OR')CO-, (R'OCH2) 2 C(R')CO-, CH 3 -N_2,(C 1 - C 3 )alkylCH=CH-CO- ,0 N-(CI C 6 )alkylCO (CI- C 6 )alkylCO- ,(C I - C 3 )alkyICONHCO-, LN(CIC6)alkyICO C N-C1- C 6 )aIkylCO- /N(,C)akO F\["N(CIC 6 )alky]CO N CHY-N (C - C 6 )alkylCO- ,t-Boc-N N-(C 1 - C 6 )alkylCO-' R 0 0 2< 11 1 EtOC y, (C I- C 6 alyl WO 99/37625 PCT/US99/01325 - 139 N-(C1 - C 6 )alkylCO CH3 R " O CO R' 0 co [(C 1 - C 6 )alkyl] 2 -N-(C 1 - C 6 )alkyl CO-, or (C 1 - C 6 )alkyl-NH-(C 1 - C 6 )alkylCO-; wherein 5 m= I to3;n=0to3; Aryl is S and R Heteroaryl is X Ntr- / Sq- 0lF N 0 S N ,mX , or X2 0 N N I R' ..oN . NN ,or 0N I I 10 R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 , and R and R' are as defined above; L is hydrogen, (C 1 -C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , -NH-(C 1 15 C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2 NH 2 ,-SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, X C O N H - Y C O N H - Y CONH /CONH- ~~~ Y S 0 WO 99/37625 PCT/US99/01325 - 140 M is Yq Y N S IN 0N N 101 R' N N N IR' I I R'-N N- - OCO-N N , N tBoc -N N- 0 N- N /--N S N- , or N(R')(R') where R' is as defined above; 5 W is O, S, NH or N(C 1 - C 3 )alkyl; Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C 1 - C 3 )alkyl, O-(Cl - C 3 )alkyl, or -CH 2 OH; and pharmaceutically acceptable salts thereof.
9. A method of treating disease conditions mediated by matrix metalloproteinase in 10 a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula 1 O II S2 &R 4 HOHN N RR 1 R R2 1 R3 WO 99/37625 PCT/US99/01325 - 141 wherein R is selected from hydrogen, (C 1 - C 3 ) alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , Cl, F, NH 2 , NH(C 1 - C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, -N(R')(R'), NO 2 , -CONH 2 , -SO2NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, wherein R' is 5 (C 1 - C 3 ) alkyl or hydrogen; R 4 is hydroxy, (C l - C 6 ) alkyl-O-, (C 1 - C 6 ) alkyl-S-, - R-, - RI 0 S R R RI - N, N , - ,-S, NN N - R ,-S R ,or -O -R', wherein R is hydrogen, halogen, cyano, methyl or -OCH 3 ; R 1 and R 2 are each, independently, hydrogen or CH 3 ; R 3 is (C 1 - C 8 )alkyl, NH 2 CH 2 CO-, (C 1 - C 6 )alkylNHCH 2 CO-, HO(CH 2 )mCO-, 10 HCO-, Aryl(CH 2 )nCO-, Heteroaryl(CH 2 )nCO-, (CI - C 3 )alkyl-O-(CH 2 )nCO-, (C 1 - C 3 )alkylCO-, (Cl - C 3 )alkylCO-NHCH 2 CO-, (C 3 - C 7 )cycloalkylCO-, (C 1 - C 3 )alkylSO 2 -, Aryl(CH 2 )nSO 2 -, Heteroaryl(CH 2 )nSO 2 -, (C 1 - C 3 )alkyl-O (CH 2 )m-SO2-, (C 1 - C 3 )alkyl-O-(CH 2 )m, (C 1 - C 3 )alkyl-O-(C 1 - C 3 )alkyl-O-(Cl C 3 )alkyl, HO-(C 1 - C 3 )alkyl-O-(C 1 - C 3 )alkyl, Aryl-O-CH 2 CO-, Heteroaryl-O 15 CH 2 CO-, ArylCH=CHCO-, HeteroarylCH=CHCO-, (C 1 - C 3 )alkylCH=CHCO-, Q- CH20C- 0 CH 2 OC-NHCH 2 CO 20 Aryl(C I - C 3 )alkyl, Heteroaryl(C 1 - C 3 )alkyl, ArylCH=CHCH 2 -, HeteroarylCH=CHCH 2 -, (C 1 - C 6 )alkylCH=CHCH 2 -, WO 99/37625 PCT/US99/0 1325 - 142 yy M M N 0 W co-C n CO- Y-Fl -TCO R'OCH 2 CH(OR')CO-, (R-OCH 2 ) 2 C(R')CO-, CHY-N (Cl - C 3 )alkylCH=CH-CO- ,0 N-(Cl - C 6 )alkylCO C- C 6 )alkyICO- ,(C - C 3 )alkyICONHCO-, LjN(CC~alkylCO GN(C I - C 6 )alkylCO- , N N(IC)lyC-,E -C-6akl CH 3 -NN(C - C 6 )alkyICO- ,t-Boc-N N-(Cl - C 6 )alkylCO-' 0O- 0 EtOC\,N(Cl - C 6 )alkylCO N(CI- C 6 )alkyICO->KI CH3 R 0:: GO 10 [(C 1 - C 6 )alkyl] 2 -N-(C 1 - C 6 )alkyl CO-, or (C 1 - C 6 )alkyl-NH-(C 1 C 6 )alkylCO-; wherein m = I to 3; n = 0 to 3; WO 99/37625 PCT/US99/01325 - 143 Aryl is X j and R Heteroaryl is - /7X , Xr- X N 0 S \X O N N \N ) N0 I R' I 7 5 R' R' wherein X is hydrogen, halogen, (C 1 - C 3 ) alkyl or -OCH 3 , and R and R' are as defined above; L is hydrogen, (C 1 -C 3 )alkyl, -CN, -OR', -SR', -CF 3 , -OCF 3 , C1, F, NH 2 , -NH-(C 1 10 C 3 )alkyl, -N(R')CO(C 1 - C 3 )alkyl, N(R')(R'), -NO 2 , -CONH 2 , -SO 2 NH 2 , -SO 2 N(R')(R'), -N(R')COCH 2 0-(C 1 - C 3 )alkyl, X - Y CONH- Y >CONH CONH- ,or WO 99/37625 PCT/US99/01325 - 144 M is Y N S N N 0 N N \ -N. Y y N N N IR' I R'-N N- - OCO-N , N tBoc -N N- 0 N- N S N- , or N(R')(R') where R' is as defined above; 5 W is O, S, NH or N(C 1 - C 3 )alkyl; Y is hydrogen, F, Cl, CF 3 or OCH 3 ; and X' is halogen, hydrogen, (C 1 - C 3 )alkyl, O-(C I- C 3 )alkyl, or -CH 2 OH; and pharmaceutically acceptable salts thereof. 10 10. A compound as claimed in any one of Claims 1 to 7 for use as a medicament.
11. Use of a compound as claimed in any one of Claims 1 to 7 in the preparation of a medicament for the treatment of a disease condition mediated by matrix metalloproteinases. 15
12. A process for the preparation of a compound of Formula 1 as claimed in any one of Claims 1 to 7 which comprises reacting the corresponding acid halide with hydroxylamine.
AU22402/99A 1998-01-27 1999-01-22 2,3,4,5-tetrahydro-1h-(1,4)-benzodiazepine-3-hydroxamic acids as matrix metalloproteinase inhibitors Abandoned AU2240299A (en)

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